Corticosteroid-Induced Osteoporosis

Corticosteroid-induced osteoporosis is the leading cause of secondary osteoporosis and a significant cause of morbidity in both men and women. Long-term use of even low-dose corticosteroids has been associated with increased risk of bone loss. Recent large randomized controlled trials have generated new knowledge on treatment strategies for patients with corticosteroid-induced osteoporosis. However, the majority of individuals receiving corticosteroids are not receiving prophylaxis for osteoporosis. Calcium and vitamin D should be recommended to patients initiating therapy with corticosteroids (and should be adequate for those receiving corticosteroids for less than 3 months). For those receiving corticosteroids for greater than 3 months, bisphosphonates are the therapy of choice, with both alendronate (alendronic acid) and risedronate (risedronic acid) approved by the US FDA for use in this indication. Calcitonin can be considered a second-line agent and should be reserved for patients who are intolerant of bisphosphonates or who are experiencing pain from a vertebral fracture. Hormone replacement therapy or testosterone therapy may be offered to those individuals on long-term corticosteroid treatment who are hypogonadal. Teriparatide (recombinant human parathyroid hormone 1-34) shows promise as a future anabolic agent for the prevention and treatment of patients with corticosteroid-induced osteoporosis.     

Risedronate: a clinical review

BACKGROUND: Risedronate sodium has recently been approved for the prevention and treatment of postmenopausal and corticosteroid-induced osteoporosis. METHODS: Studies of risedronate were obtained from the MEDLINE database (1966 to the present) of references using risedronate, risedronic acid, osteoporosis, and human subject as keywords. Additional references were sought from the reference lists of the articles obtained. RESULTS: Nine randomized controlled trials and 7 other clinical trials were obtained. In postmenopausal women with normal bone density, risedronate increases lumbar spine bone density and preserves femoral neck density. In postmenopausal women with prior vertebral fracture, risedronate decreases new vertebral and nonvertebral fracture incidence. In patients who experienced breast cancer and who have chemotherapy-induced menopause, risedronate preserves bone. Risedronate prevents vertebral bone loss in patients beginning long-term corticosteroid therapy. Risedronate decreases pagetic bone pain and induces radiological improvement in pagetic lesions. Risedronate induces normalization of biochemical abnormalities and may be more effective than etidronate disodium for Paget disease. Only one study, a trial in patients with postmenopausal osteoporosis using a low dose (2.5 mg) of risedronate, did not have a positive result. Adverse effects in patients with postmenopausal osteoporosis, breast cancer, and Paget disease and in those taking corticosteroids are similar to those of patients taking placebo, and do not include notable upper gastrointestinal tract adverse event rates or serious adverse events. CONCLUSIONS: Risedronate prevents postmenopausal bone loss, decreases fracture in those with established postmenopausal osteoporosis, effectively treats Paget disease, and prevents corticosteroid-induced bone loss. Long-term toxic effects and efficacy, particularly fracture end point data, are unknown. Also undefined are optimal duration of therapy, potential for use in combination with other agents, and direct comparison with other bisphosphonates used for osteoporosis.     

Prevention and treatment of osteoporosis in patients with inflammatory bowel disease

Osteopenia or osteoporosis is common in patients with inflammatory bowel disease. The use of corticosteroids contributes to the decline in bone loss; however, osteoporosis may develop in patients with inflammatory bowel disease independent of corticosteroid use. Risk factors for the development of low bone mass in patients with inflammatory bowel disease include the general risk factors for osteoporosis as well as additional factors such as the presence of chronic inflammation, use of corticosteroids and other pharmaceuticals, and nutritional deficiencies as the result of small bowel disease or small bowel resections. Despite the high prevalence, few patients are entered into prophylactic regimens to prevent corticosteroid-induced bone loss. The American College of Rheumatology has recently published recommendations for the prevention and treatment of corticosteroid-induced osteoporosis. In this article, we highlight the special risks for osteoporosis in patients with IBD and adapt the recommendations for prevention and treatment of osteoporosis to this clinical setting.     

Ostéoporose cortico-induite

Corticosteroid-induced osteoporosis is the most common form of secondary osteoporosis and the first cause in young people. Bone loss occurs early after the initiation of corticosteroid therapy and is correlated to dosage and treatment duration. Osteoporosis prevention is justified in all subjects who begin glucocorticoids, since the underlying inflammation has itself a deleterious bone impact. Bone loss magnitude is variable and there is no clearly identified predictor of the individual risk of fracture. Prevention or treatment of osteoporosis should be considered in all patients who received a daily dose of at least 7.5 mg equivalent prednisone and a treatment that is expected to last at least 3 months. Bisphosphonates and the anabolic agent parathyroid hormone (1–34) have shown their efficacy in the treatment of corticosteroid-induced osteoporosis. Recent international guidelines are available and should guide management of corticosteroid-induced osteoporosis that remains under-diagnosed and under-treated. Duration of anti-osteoporotic treatment should be discussed at the individual level, depending on the subject's characteristics, and on the underlying inflammation evolution.     

Bone and glucocorticoids

Corticosteroid-induced osteoporosis is the most common form of secondary osteoporosis and the most frequent cause of osteoporosis in young people. Bone loss and fracture risk increase rapidly after the initiation of corticosteroid therapy and are proportional to dose and treatment duration. The increase in fracture risk is not fully assessed by bone mineral density measurement, as it is also related to impaired bone quality and increased risk of falls. Prevention should be considered in all patients beginning corticosteroid therapy, especially as the underlying inflammation in itself impairs bone quality. Bisphosphonates and teriparatide have shown efficacy in the treatment of corticosteroid-induced osteoporosis. Several national and international guidelines are available to improve management of corticosteroid-induced osteoporosis, which remains inadequate. Duration of anti-osteoporotic treatment should be discussed at the individual level, depending on the subject's characteristics and on the progression of the underlying inflammation.     

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.     

Corticosteroid osteoporosis

Corticosteroids are widely used and effective agents for the control of many inflammatory diseases, but corticosteroid osteoporosis is a common problem associated with their long term high dose use. Prevention of corticosteroid osteoporosis is preferable to treatment of established corticosteroid bone loss. Several large double-blind controlled clinical trials in patients with corticosteroid osteoporosis have recently been published that provide new insights into its treatment. Based upon available evidence, the rank order of choice for prophylaxis would be a bisphosphonate followed by a vitamin D metabolite or an oestrogen type medication. Calcium alone appears to be unable to prevent rapid bone loss in patients starting corticosteroids, especially with prednisolone doses at 10 mg a day or greater. If an active vitamin D metabolite is used, calcium supplementation should be avoided unless dietary calcium intake is low. Hormone replacement therapy should be considered if hypogonadism is present. Since vertebral fracture is a common and important complication of high dose corticosteroid therapy, these findings suggest that rapid bone loss and hence fractures, can be prevented by prophylactic treatment. Although the follow-up data is limited, it is likely that such therapy needs to be continued beyond 12 months whilst patients continue significant doses of corticosteroid therapy.     

Corticosteroid osteoporosis

Summary Corticosteroids are widely used in the treatment of patients with chronic inflammatory diseases. Since the most rapid bone loss occurs in the first 12-24 months after commencing high dose corticosteroids, it is important to consider two different therapeutic situations, (a) prevention in patients starting corticosteroids and (b) treatment of patients on chronic corticosteroids who will already have some significant degree of corticosteroid related bone loss.¶ An adequate calcium intake is recommended and any contributing factors to osteoporosis should be treated. A bone density will give information about the future risk of osteoporotic fracture and the need for active pharmacological treatment. Patients commencing high dose long-term corticosteroid therapy should be treated prophylactically with a bisphosphonate and/or active vitamin D metabolites (alphacalcidol or calcitriol) and the treatment may need to be continued for 1-2 years. Patients on chronic corticosteroids may improve their bone density by treatment with bisphosphonates and vitamin D metabolites (including the calciferols). In postmenopausal women, concomitant use of estrogen replacement therapy is also appropriate. It is important in a patient on long-term therapy to review the need for continuing treatment or the possibility of dosage reduction.     

Osteoporosis associated with rheumatoid arthritis: pathogenesis and management

Rheumatoid arthritis is associated with both localized and generalized osteoporosis. Localized osteoporosis can be considered to be caused by local disease mechanisms, including the generation of factors from activation of the cytokine pathway. The etiology of generalized osteoporosis has been difficult to elucidate, particularly because of the lack of sensitive techniques to measure bone mineral density. The introduction of single- and dual-photon absorptiometry and quantitative computed tomography has allowed more accurate assessment of bone mineral density. In general, bone mineral density loss at appendicular sites does not correlate well with axial bone density loss. Corticosteroid treatment exaggerates the development of osteoporosis in up to 40% of patients with rheumatoid arthritis. Sex hormone status, physical activity, disease duration, and functional class are all significant predictors for the development of osteoporosis. Current therapy for prevention and treatment is based largely on theoretical considerations. Physical activity should be encouraged once acute joint inflammation has settled. Postmenopausal women and amenorrheic premenopausal women will benefit from cyclical estrogen replacement. Patients with low serum 1,25-dihydroxy vitamin D3 levels, and males with low serum testosterone levels, are candidates for replacement therapy with the appropriate hormones. In patients who are receiving corticosteroids the dose should be limited, and oral calcium supplements are of benefit. The use of the newer corticosteroid deflazacort, and disease-modifying immunosuppressive drugs, are discussed. Other therapeutic options which should be considered, although published trials are scarce, are calcitonin and the diphosphonates. Further studies are awaited concerning the optimum prevention and treatment of osteoporosis associated with rheumatoid arthritis.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Management of corticosteroid-induced osteoporosis

Corticosteroid (CS) therapy is widely used in the treatment of rheumatic diseases. Osteoporosis remains one of its major complications. The risk of low bone mineral density (BMD) and fracture may be already increased in some of the rheumatic diseases, regardless of CS therapy. However, in spite of this, preventative treatment for osteoporosis in patients on CS remains low. Patients on or about to start CS use for more than 6 months are at risk of corticosteroid-induced osteoporosis (CIOP). The pathogenesis of CIOP differs from post-menopausal osteoporosis in that bone formation is said to be more suppressed compared with bone resorption. The diagnosis of CIOP can be made on clinical risk factors and may not require measurement of BMD. Many agents used in post-menopausal osteoporosis such as activated vitamin D products, hormone replacement therapy, fluoride, calcitonin and the bisphosphonates have been shown to maintain or improve BMD in CIOP. However, there are few data on the reduction in fracture rates in CIOP, but the bisphosphonates seem the most promising in this regard.     

Treatment of osteoporosis with bisphosphonates

Bisphosphonates are safe and effective agents for treatment and prevention of osteoporosis. Alendronate and risedronate are the best studied of all agents for osteoporosis in terms of efficacy and safety. They increase bone mass. In patients who have established osteoporosis, they reduce the risk of vertebral fractures. They are the only agents shown in prospective trials to reduce the risk of hip fractures and other nonvertebral fractures. They are approved by the US FDA for prevention of bone loss in recently menopausal women, for treatment of postmenopausal osteoporosis, and for management of glucocorticoid-induced bone loss. Other bisphosphonates (e.g., etidronate for oral use, pamidronate for intravenous infusion) are also available and can be used off-label for patients who cannot tolerate approved agents. Bisphosphonates combined with estrogen produce greater gains in bone mass compared with either agent used alone; whether there is a greater benefit of combination therapy on fracture risk is not clear. Combining a bisphosphonate with raloxifene or calcitonin is probably safe, although data on effectiveness are lacking.     

Osteoporosis in systemic lupus erythematosus: prevention and treatment

The patient with systemic lupus erythematosus (SLE) is at risk of osteoporosis through several factors: the inflammatory disease itself, disease-related co-morbidity, and its treatment. Bone loss is apparent early in the disease and this may be confounded primarily by treatment with corticosteroids. Patients should be assessed for additional risk factors for osteoporosis and general lifestyle measures adopted. Bone mineral density measurement should be considered in SLE patients at high risk of osteoporosis, particularly those starting corticosteroids and in postmenopausal women. Calcium and vitamin D supplementation provide general prophylaxis and are a suitable first-line option. Hormone replacement should be used in hypogondal subjects unless contra-indicated. In subjects at high fracture risk, particularly in postmenopausal women, bisphosphonate therapy should be considered as these agents have been shown to significantly reduce vertebral fracture risk. These measures should reduce the burden of osteoporosis and fracture in patients with lupus.     

Osteoporosis in rheumatoid arthritis--significance of alfacalcidol in prevention and therapy

Besides localised osteopenia, patients with rheumatoid arthritis (RA) with or without corticosteroids develop in 30-50% osteoporosis induced by several factors and thus a higher risk of fractures. Bone loss appears very early and correlates directly with disease activity and also later with the negative effects of restrictive mobility. Corticosteroids reduce as a pathogenetic co-factor intestinal calcium absorption and increase renal calcium excretion resulting in compensatory increased PTH-release and increased sensitivity of bone to PTH. In addition, corticosteroids inhibit osteoblast function as well as the favourable effects of growth factors and sex hormones on bone. It has recently been recognised that the expression of D-hormone receptors (VDRs) is suppressed by these medications and that corticosteroids probably induce VDR disorders. The negative influence of corticosteroids on muscle strength (indirectly--via increased PTH-levels, lowered IGF-1-levels or reduced D-hormone activity) is a feature which has been underestimated. The demonstrated drop in 1,25(OH)2D3 (D-hormone) levels in patients with RA in correlation with C-reactive protein (CRP) is of significance in the pathogenesis of RA-induced osteoporosis and could further promote the process of inflammation. There is a general consensus that cytokines (e.g. IL-1, IL-6, IL-12, TNF-alpha) induce bone resorption in inflammatory rheumatic diseases. There are, however, new findings which show that cytokines like TNF-alpha also interfere with bone formation by promoting apoptosis of osteoblasts and reduce the muscle strength, too. D-hormone preparations (alfacalcidol, calcitriol) possess immunoregulatory effects in vitro and in vivo by inhibiting the cytokines IL-1, IL-6, TNF-alpha and particularly IL-12. At the cellular level, D-hormone reduces the expression of Th1 helper cells directly or indirectly by inhibition of IL-12 from monocytes. Therapy with alfacalcidol or calcitriol results in increased production of Th2 helper cells which produce bone protective cytokines like IL-4 and IL-10. It is important to know that D-hormone protects osteoblasts against TNF-alpha-induced cell death. After conversion to D-hormone in the liver and bone, alfacalcidol antagonises the above described pathogenetic factors of the corticosteroids. D-hormone is one of the body's own immunoregulators, which is produced in macrophages in cases of need to reduce immunological overreactions in a feed-back loop. Improved understanding of the pathogenesis of corticosteroid-induced osteoporosis and of the pharmacological effects of alfacalcidol in this type of iatrogenic bone loss as well as the results of specific animal models simulating bone loss in inflammatory diseases explain the favourable effects of alfacalcidol in this indication. Various clinical studies have demonstrated clearly that alfacalcidol retards corticosteroid-induced bone loss in contrast to plain vitamin D. Due to its immunomodulating properties, alfacalcidol is particularly suitable for RA-induced bone loss and for the prevention of transplantation osteoporosis, and an adjuvant contribution to the disease-modifying therapy of RA and to the immunosuppressive therapy after transplantation can not be excluded.     

Glucocorticoid-induced osteoporosis

This article attempts to evaluate the results of several recently published clinical trials of drugs used in the treatment and prevention of glucocorticoid-induced osteoporosis. Despite our lack of understanding regarding the biological mechanisms that lead to glucocorticoid-induced bone loss, effective therapy has been developed. Bisphosphonates have demonstrated significant treatment benefits and should be considered the therapy of choice for both the treatment and prevention of glucocorticoid-induced osteoporosis.     

The prevention of corticosteroid-induced bone loss with intermittent cyclical etidronate.

A prospective, randomised, double-blind, placebo controlled primary prevention trial was undertaken in 28 patients commencing low to moderate doses of corticosteroids for the first time. Patients were randomised to intermittent cyclical etidronate (400 mg daily for 2 weeks) and calcium (500 mg daily for 11 weeks) or intermittent cyclical placebo with calcium. After 52 weeks of treatment, lumbar spine BMD increased by 1.8% in the etidronate group, while it decreased by 3.7% in the placebo group. The differences in bone loss rate were statistically significant (p<0.01) at both 6 and 12 months. Similar trends were observed at the proximal femur, but differences were not statistically significant. These results suggest that intermittent cyclical etidronate therapy is effective in the primary prevention of corticosteroid-induced bone loss at the lumbar spine.     

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.     

Ostéoporose cortisonique: de la physiopathologie au traitement

Corticosteroid-induced osteoporosis, the principal cause of "secondary" osteoporosis, is usually observed in patients under prolonged systemic corticosteroid therapy and results from the multiple effects exerted by these drugs on bone cell metabolism. Corticosteroids reduce the intestinal absorption of calcium and its tubular reabsorption, thereby negativating the calcium balance and inducing a parathyroid reaction. This reaction is responsible for an increase in bone cell remodelling, but the main manifestation of the direct effect of corticosteroids on bone is osteoblast depression, so that there is disparity between bone resorption and formation, which in turn is responsible for bone tissue deficit. Sex hormone deficiency (due to menopause or treatment) and lack of physical activities (due to the causal disease or to iatrogenic myopathy) amplify bone rarefaction. By quantifying the bone loss, modern densitometry methods provide an early risk evaluation. Osteoporosis of varying intensity exposes some 20% of patients to fractures, vertebral collapse and rib fractures. Preventive measures are always recommended, including minimal effective dose corticosteroid therapy, sodium-free diet, calcium and vitamin D supplement, sex hormone replacement and pursuance of physical activities. Once the stage of fractures by osteoporosis has been reached, the "curative" treatment aims at reducing the incidence of new fractures, either by slowing down osteoclast resorption, or by restoring the bone tissue reserve through stimulation of the osteoblasts. The usefulness of these therapeutic measures in the preventive treatment of corticosteroid-induced osteoporosis remains controverted.     

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.