Management of corticosteroid-induced osteoporosis

OBJECTIVES: To educate scientists and health care providers about the effects of corticosteroids on bone, and advise clinicians of the appropriate treatments for patients receiving corticosteroids. METHODS: This review summarizes the pathophysiology of corticosteroid-induced osteoporosis, describes the assessment methods used to evaluate this condition, examines the results of clinical trials of drugs, and explores a practical approach to the management of corticosteroid-induced osteoporosis based on data collected from published articles. RESULTS: Despite our lack of understanding about the biological mechanisms leading to corticosteroid-induced bone loss, effective therapy has been developed. Bisphosphonate therapy is beneficial in both the prevention and treatment of corticosteroid-induced osteoporosis. The data for the bisphosphonates are more compelling than for any other agent. For patients who have been treated but continue to lose bone, hormone replacement therapy, calcitonin, fluoride, or anabolic hormones should be considered. Calcium should be used only as an adjunctive therapy in the treatment or prevention of corticosteroid-induced bone loss and should be administered in combination with other agents. Conclusions: Bisphosphonates have shown significant treatment benefit and are the agents of choice for both the treatment and prevention of corticosteroid-induced osteoporosis.     

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.     

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.     

Bisphosphonates in Corticosteroid-Induced Osteoporosis

Corticosteroid osteoporosis is a common clinical problem with the risk of fracture, highest in postmenopausal women. The first choice for prevention is a potent oral bisphosphonate such as alendronate or risedronate. In patients intolerant of oral bisphosphonates, intravenous bisphosphonates should be used. Prophylactic therapy should be continued whilst patients continue significant doses of corticosteroid therapy. In patients receiving chronic low-dose corticosteroids where the BMD is substantially reduced, other therapies such as PTH should be considered, followed by a bisphosphonate.     

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.     

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.     

Drug insight: Existing and emerging therapies for osteoporosis

Osteoporosis is a major public health problem that is characterized by microarchitectural deterioration, low bone mass, and increased risk of fractures. Currently, many women and men affected with this disease are not diagnosed or treated. As osteoporosis is often clinically silent, risk-factor assessment and measurement of BMD are needed to identify those who may benefit from osteoporosis therapy. Although adequate daily intake of calcium and vitamin D, and regular weight-bearing exercise are important for skeletal health, they are not adequate treatments for individuals with osteoporosis. Therapies approved for treatment and/or prevention of osteoporosis in the United States include oral bisphosphonates (alendronate, ibandronate and risedronate), calcitonin, estrogens, teriparatide (parathyroid hormone fragment [1-34]), and raloxifene. For most patients, oral bisphosphonates are the treatment of choice, given the large-scale randomized-trial data demonstrating efficacy in fracture reduction, although bisphosphonates that reduce spine and nonspine fractures (e.g. alendronate and risedronate) are preferred. For high-risk patients (those with very low bone density, or with fractures), teriparatide therapy for 2 years should be considered. The treatment paradigm for osteoporosis will evolve further as promising new treatments progress through clinical development.     

Fragility fractures and the osteoporosis care gap: an international phenomenon

OBJECTIVES: To describe practice patterns in the management of osteoporosis after fragility fracture. METHODS: Systematic review of articles in MEDLINE, EMBASE, Cochrane, and CINAHL databases (1996 to February 2005). Diagnostic outcomes included clinical osteoporosis diagnoses, laboratory tests, and bone density scans. Treatment outcomes included initiation of calcium, vitamin D, hormone replacement therapy, bisphosphonates, calcitonin, raloxifene and falls assessments. RESULTS: Thirty-five studies met our inclusion criteria and demonstrated that adults who experience fragility fracture are not receiving osteoporosis management. An osteoporosis diagnosis was reported in 1 to 45% of patients with fractures; laboratory tests were ordered for 1 to 49% and 1 to 32% of patients had bone density scans. Calcium/vitamin D and pharmacological therapy was reported in 2 to 62% and 1 to 65% of patients, respectively. Osteoporosis treatment was recommended more often in women than men, and more often in patients with vertebral fractures than in patients with nonvertebral fractures. Older patients were more likely to be diagnosed with osteoporosis, but treatment was more likely in younger patients. A history of prior fracture was reported in 7 to 67% of patients. Between 1 and 22% of patients had a subsequent fracture during follow-up periods of 6 months to 5 years. Falls assessments were not often reported; when they were, they were infrequently performed. A greater proportion of patients were diagnosed/treated during follow-up studies than in studies evaluating diagnosis/treatment on discharge from acute care. CONCLUSIONS: The majority of individuals who sustain fragility fractures are not receiving adequate osteoporosis management. Future research should address barriers to appropriate management and the efficacy of implementation strategies designed to close the osteoporosis care gap. RELEVANCE: This article is of particular importance to health care professionals who provide care for patients with fragility fracture.     

How to prevent steroid induced osteoporosis

The first choice for prevention of corticosteroid osteoporosis is a potent oral bisphosphonate-for example, alendronate or risedronate. Intravenous bisphosphonates should be considered for patients intolerant of the oral route. For patients receiving chronic low dose corticosteroids treatment with calcium and vitamin D may prevent further bone loss. Use of parathyroid hormone is promising.     

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.     

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.     

Effect of the long-term use of inhaled corticosteroids on bone mineral density in asthmatic women

OBJECTIVE: Inhaled corticosteroids have become a key element in the maintenance treatment of bronchial asthma. Recent studies have shown that administration of inhaled corticosteroids is associated with evidence of derangement in bone turnover. Therefore, we studied the bone mineral density (BMD) of asthmatic women receiving long-term inhaled corticosteroids and compared them with healthy individuals matched for age, sex, menopausal status and body mass index. METHODOLOGY: Thirty-two female patients with bronchial asthma, who had been using inhaled corticosteroids (beclomethasone dipropionate 750-1500 microg/day) regularly for at least 3 months, were included in the study. Bone mineral density measurements were done with dual X-ray absorptiometry in the lumbar area of the spine and the hip. Detailed laboratory examination was also done for the patients and 26 controls. RESULTS: There was a significant decrease in BMD of the patient group at the lumbar region and femur as compared with normal controls. In the patients there was a significant negative correlation between the duration of therapy, daily and cumulative doses, and BMD at the lumbar region but not BMD at the femur. CONCLUSIONS: These results indicate that long-term use of inhaled corticosteroids is associated with significant bone loss in asthmatic women and is especially related to the duration of therapy. Therefore, it is necessary to appropriately screen and give prophylactic treatment to those who are likely to develop osteoporosis from inhaled corticosteroid treatment.     

Oral Bisphosphonate-Related Osteonecrosis of the Jaw: Incidence,Clinical Features,Prevention, and Treatment Recommendations

Biphosphonate-related osteonecrosis of the jaw (BRONJ) is a devastating side effect of oral bisphosphonates associated with patient morbidity and high financial burden to health services. BRONJ is usually associated with parenteral use of bisphosphonates in oncologic patients, but its incidence among individuals with osteoporosis who take oral bisphosphonates is on the rise. In the absence of definitive treatment for BRONJ, every effort should be made toward its prevention. The patients must be informed about the extremely small but proven risk of oral BRONJ and be recommended to undergo periodic dental evaluation and meticulous oral hygiene. Once BRONJ occurs, long-term antibiotic therapy and superficial curettage may be beneficial.     

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.     

Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use

All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog, teriparatide [recombinant human PTH(1-34)], represent a new class of anabolic therapies for the treatment of severe osteoporosis, having the potential to improve skeletal microarchitecture. Significant reductions in both vertebral and appendicular fracture rates have been demonstrated in the phase III trial of teriparatide, involving elderly women with at least one prevalent vertebral fracture before the onset of therapy. However, there is as yet no evidence that the antifracture efficacy of PTH will be superior to the bisphosphonates, whereas cost-utility estimates suggest that teriparatide is significantly more expensive. Teriparatide should be considered as treatment for postmenopausal women and men with severe osteoporosis, as well as for patients with established glucocorticoid-induced osteoporosis who require long-term steroid treatment. Teriparatide should also be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores < or = 3.5). Teriparatide therapy is not recommended for more than 2 yr, based, in part, on the induction of osteosarcoma in a rat model of carcinogenicity. Total daily calcium intake from both supplements and dietary sources should be limited to 1500 mg together with adequate vitamin D intake (< or =1000 U/d). Monitoring of serum calcium may be safely limited to measurement after 1 month of treatment; mild hypercalcemia may be treated by withdrawing dietary calcium supplements, reducing the dosing frequency of PTH, or both. At present, concurrent therapy with antiresorptive therapy, particularly bisphosphonates, should be avoided, although sequential therapy with such agents may consolidate the beneficial effects upon the skeleton after PTH is discontinued.     

Bone mineral density in juvenile dermatomyositis: assessment using dual x-ray absorptiometry

OBJECTIVE: To determine the bone mineral density (BMD) status of our juvenile dermatomyositis (DM) population and to compare the frequency of osteopenia in patients with active disease requiring corticosteroids with that in patients with inactive disease who are not receiving corticosteroids. METHODS: Medical charts of all children diagnosed as having juvenile DM at our institution between 1989 and 1999 were reviewed for demographic and clinical data, including disease activity and duration of corticosteroid therapy. BMD measurements of the lumbar spine (L1-L4) were performed using dual x-ray absorptiometry (DXA). Z scores were calculated from the BMD data for comparison with published normative data. RESULTS: A total of 15 patients were assessed: 10 with active disease, and 5 with inactive disease who had not taken corticosteroids for an average of 6.0 years (range 3.4-8.1 years). Baseline BMD measurements demonstrated osteopenia or frank osteoporosis in the majority of patients, including 6 of the 10 patients with active disease and 4 of the 5 patients whose disease was in remission. Fourteen patients had serial BMD measurements. Persistent or worsening osteopenia was documented in all patients who had ongoing active disease, except for 3 patients who had been treated with bisphosphonates because of vertebral compression fractures. CONCLUSION: Osteopenia is common in patients with juvenile DM, and it usually worsens with ongoing disease. It can persist for many years after the disease enters remission. Bisphosphonates appeared to beneficially affect bone mineralization in our patients. Treatment to prevent the long-term complications of osteoporosis in patients with juvenile DM should be considered and requires further study.     

Bisphosphonates and osteonecrosis of the jaw

Bisphosphonates are used worldwide as a successful treatment for people with osteoporosis, which is the major underlying cause of fractures in postmenopausal women and older adults. These agents are successful at increasing bone mass and bone trabecular thickness, decreasing the risk of fracture, and decreasing bone pain, enabling individuals to have better quality of life. Bisphosphonates are also used to treat multiple myeloma, bone metastasis, and Paget's disease; however, bisphosphonate treatment may result in negative side effects, including osteonecrosis of the jaw (ONJ). ONJ involves necrotic, exposed bone in the jaw, pain, possible secondary infection, swelling, painful lesions, and various dysesthesias, although less-severe cases may be asymptomatic. First-generation bisphosphonates, which do not contain nitrogen, are metabolized into a nonfunctional, cytotoxic analogue of adenosine triphosphate and cause osteoclast death by starvation. Second-generation bisphosphonates are nitrogen-containing agents; these inhibit osteoclast vesicular trafficking, membrane ruffling, morphology, and cytoskeletal arrangement by inhibiting farnesyl diphosphate synthase in the mevalonate pathway. Physicians treating older adults with osteoporosis and cancer should work together with dental practitioners, pharmacists, and other clinicians to inform individuals receiving bisphosphonates of their possible side effects and to suggest precautionary steps that may minimize the risk of osteonecrosis, particularly of the jaw. These include practicing good oral hygiene; scheduling regular dental examinations and cleanings; and cautioning people who are scheduling treatment for periodontal disease, oral and maxillofacial therapy, endodontics, implant placement, restorative dentistry, and prosthodontics. Recommendations for management of people with ONJ include an oral rinse, such as chlorhexidine, and antibiotics.     

阿伦膦酸盐预防激素相关性骨量丢失的前瞻性研究

目的 研究阿伦膦酸盐预防激素相关性骨质疏松的作用.方法 将21例需要长期服用糖皮质激素的风湿病患者随机分为治疗组和对照组.对照组在应用糖皮质激素治疗同时给予乐力(氨基酸鳌合钙加维生素D)1粒,每天2次,口服;治疗组在对照组药物的基础上,加用阿伦膦酸盐10 mg,每天1次或70 mg,每周1次,口服.所有患者在治疗前和治疗后3、6、12月,应用双能X线吸收法测定腰椎及股骨颈的骨密度(BMD).结果 对照组在糖皮质激素治疗后3、6、12个月BMD与自身治疗前比较明显下降(P<0.01);治疗组腰椎的BMD与自身治疗前比较有上升趋势(12个月时有统计学差异,P<0.05),股骨颈的BMD治疗后3、6个月与自身治疗前比无变化(P>0.05),12个月有轻度降低(P<0.05).结论 单予钙剂加维生素D不能有效预防糖皮质激素相关性骨质疏松的发生,加用阿伦膦酸盐则可有效延缓糖皮质激素相关性骨量丢失.