Glucocorticoid-induced osteoporosis

Glucocorticoid-induced osteoporosis (GIOP) is a challenging problem. Several rheumatic disorders necessitate long-term glucocorticoid therapy. Therefore, it is a topic of great interest to practicing rheumatologists. During the first 6–12 months of glucocorticoid therapy there is an initial loss of 3–27% of bone mineral density (BMD). It is estimated that 50% of chronic glucocorticoid users will develop bone loss leading to fracture, especially of spine and neck of femur. For a given BMD, the risk of fracture is higher in GIOP than in postmenopausal osteoporosis. American College of Rheumatology has laid down guidelines for the prevention and treatment of GIOP. Various facts and current therapies aimed at its prevention and reversal are discussed in this review article.     

Recommendations for the registration of agents to be used in the prevention and treatment of glucocorticoid-induced osteoporosis: updated recommendations from the Group for the Respect of Ethics and Excellence in Science

OBJECTIVES: The Group for the Respect and Excellence in Science (GREES) has reviewed and updated their recommendations for clinical trials to evaluate the efficacy and safety of new chemical entities to be used in the treatment and prevention of glucocorticoid-induced osteoporosis (GIOP). METHODS: Consensus discussion of the committee. RESULTS: With the exception of steroid use posttransplantation, there is no need to differentiate between underlying diseases. Prevention and treatment for GIOP are dependent on exposure to glucocorticoids rather than T-scores as in postmenopausal osteoporosis (PMO). If fracture data are obtained for PMO, it need not be repeated for GIOP, relying instead on bone mineral density (BMD) trials of at least 1 year. GREES recommends several changes in the previous guidance for GIOP. The committee saw no need to repeat preclinical studies if those have been previously done to assure bone quality in PMO. Similarly, phase I and phase II trials, if careful dose selection has been done for PMO, should not be repeated. The "prevention" and "treatment" claims should remain. Since the most recent evidence suggests significant increase in fracture risk for daily doses of prednisone of 5 mg/day or equivalent, clinical trials should concentrate on patients receiving at least this daily dosage. The emergence of bisphosphonates as the reference treatment, together with the rapid bone loss and high fracture incidence in glucocorticoid users, necessitates recommending a noninferiority trial design with lumbar spine BMD as the primary endpoint after 1 year. CONCLUSIONS: Registration of new chemical entities to be used in the management of GIOP should be granted, based on a 1-year noninferiority trial, using BMD as primary outcome and alendronate or risedronate as comparator. Demonstration of antifracture efficacy should have been previously demonstrated in PMO.     

Glucocorticoid-induced osteoporosis in men

Osteoporosis and fractures are a common consequence of glucocorticoid therapy for inflammatory disorders. Men fracture approximately 10 yr later in life than women and receive less attention as regards osteoporosis risk, including in glucocorticoid-induced osteoporosis (GIOP). In addition, while men are less likely to have certain rheumatologic disorders often treated with glucocorticoids, men are more likely to have chronic obstructive pulmonary disease, inflammatory bowel disease, and organ transplantation as reasons for use of oral glucocorticoids. Attempts to improve recognition of GIOP in general have not been successful, and since men are considered less at risk for osteoporosis in general, attention to men with GIOP is even less. Evaluation of GIOP is similar in men and women, and most modern treatment studies of GIOP have included men. Thus, alendronate, risedronate, and zoledronic acid are Food and Drug Administration (FDA)-approved bisphosphonates for GIOP in men. Teriparatide is also FDA-approved for GIOP. In one 36-month trial of teriparatide vs alendronate for GIOP in men and women, the anabolic agent led to a greater increase in bone density and was associated with a lower incidence of morphologic vertebral fractures. Thus, while good management is available for GIOP, recognition of men at risk is the most important step in improving outcomes.     

Suggested guidelines for evaluation and treatment of glucocorticoid-induced osteoporosis for the Department of Veterans Affairs

BACKGROUND: Glucocorticoid-induced osteoporosis is an important disorder in the predominantly male US veteran population. Department of Veterans Affairs facilities vary considerably in evaluation and management of glucocorticoid-induced osteoporosis. METHODS: We suggest how evaluation and management can take place in medical centers with and without bone mineral density measurements by dual energy x-ray absorptiometry (DXA). The proposed guidelines can be applied to other health care systems. RESULTS: Use of DXA can help determine fracture risk for patients taking glucocorticoid therapy and for those starting therapy for at least 3 months. Patients with low bone mineral density should be treated with a bisphosponate as should all patients about to start prednisone treatment at a dose of 7.5 mg/d or more. In facilities without DXA, most patients should be treated with bisphosphonates, the cost of which is about $30 to $35 per month. In addition, the use of urinary calcium measurements is encouraged to determine which patients might benefit from augmented vitamin D and calcium supplementation. CONCLUSION: Attention to fracture risk assessment in patients undergoing glucocorticoid therapy and timely bisphosphonate treatment should lead to fewer fractures.     

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.     

Advances in the management of corticosteroid-induced osteoporosis with bisphosphonates

Corticosteroids are widely used as anti-inflammatory and immunosuppressive agents to treat a variety of chronic conditions. Long-term (>1 year) corticosteroid use can lead to bone loss, and therefore, osteopenia or osteoporosis. Corticosteroid-induced osteoporosis (CIO) leads to increased bone fragility and subsequently fractures, which, in turn, lead to a loss of physical, emotional and social health for the patient and increased costs for healthcare providers. A wealth of data exists demonstrating the efficacy of the oral bisphosphonates, etidronate, alendronate and risedronate in increasing bone mineral density in patients with CIO or preventing bone loss in patients commencing corticosteroid therapy. Data regarding fracture prevention are less clear, as statistically significant reductions in the incidence of fractures have only been reported for patient subgroups or meta-analyses. However, many treatment guidelines recommend the use of oral bisphosphonates for the prevention and treatment of CIO. These guidelines are, however, not reflected in prescribing practice, and the majority of patients do not receive adequate concomitant therapy. This review summarizes the available data for bisphosphonates in CIO. Therapeutic adherence with oral bisphosphonates is an issue, with approximately 50% of patients discontinuing therapy within the first year. The primary reasons for this are poor gastrointestinal tolerability and the frequency with which complex dosing requirements must be followed. The inconvenience of taking daily or weekly bisphosphonate therapy is of particular importance in patients with CIO who may be regularly taking several other medications. Data obtained in studies with ibandronate indicate that bisphosphonate administration by rapid intravenous injection provides an effective, well-tolerated and practical alternative to current oral regimens in the management of patients with CIO.     

Prevention of postmenopausal osteoporosis with pharmacological therapy: practice and possibilities

Postmenopausal osteoporosis (PMO) is a common disease that will become more prevalent in the future, with costly implications for public health. Prevention of the disease and its consequences, namely fractures, is therefore, important for both the individual and society. This review discusses: the goals of PMO prevention; the identification of women at risk, including the use of bone mineral density and bone turnover markers; the relevance in the prevention setting of various current guidelines for PMO management; recent data on therapeutic options for the treatment and prevention of PMO, in particular bisphosphonates, hormone replacement therapy and several other new pharmacological agents. It concludes that it is crucial for PMO prevention to start before disease onset and that, in the light of recent evidence, the existing guidelines need updating if they are to continue to be relevant.     

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.     

Clinical Question: What is the best approach to managing glucocorticoid‐induced osteoporosis?

Glucocorticoid-induced osteoporosis is common, and the resulting fractures cause significant morbidity and mortality. Rapid bone loss and increased fracture risk occur soon after the initiation of glucocorticoid therapy and are dose dependent. The increase in fracture risk is partly independent of bone mineral density, probably as a result of changes in bone material properties and increased risk of falling. Fracture risk can be assessed using the FRAX algorithm, although risk may be underestimated in patients taking higher doses of glucocorticoids. Because of the rapidity of bone loss and increase in fracture risk after the start of glucocorticoid therapy, primary prevention should be advised in high-risk individuals, for example older women and men, individuals with a previous fracture history and those with low bone mineral density. Bisphosphonates are the front-line choice for the prevention of fracture in the majority of glucocorticoid-treated patients, with teriparatide as a second-line option. Calcium and vitamin D supplements should be co-prescribed unless there is evidence of an adequate dietary calcium intake and vitamin D status.     

Barriers in the management of glucocorticoid-induced osteoporosis

OBJECTIVE: To determine present practice for the management of glucocorticoid-induced osteoporosis (GIOP) in veterans; to characterize provider knowledge, beliefs, and practice behaviors regarding management of GIOP; and to identify potential barriers and interventions in the management of GIOP. METHODS: To characterize current management of GIOP in an academic veterans administration medical center, we conducted a retrospective chart review of 100 patients who were prescribed a 90-day supply of prednisone. To assess clinicians' knowledge of GIOP clinical guidelines and perceptions of GIOP management, primary care clinicians and subspecialists completed a questionnaire and participated in focus groups. RESULTS: Chart review revealed that only 32 of 100 patients receiving long-term glucocorticoid treatment underwent bone mineral density testing, and only 32 patients were prescribed the recommended calcium supplements. Of the 23 providers who completed the questionnaire and participated in the focus groups, 4 correctly identified both the dose and duration of glucocorticoid use at which GIOP prevention measures should be instituted. Common GIOP management barriers cited by participants were lack of knowledge, having limited time during the clinic visit to address all problems, patient nonadherence, and system problems. The most commonly mentioned potential interventions were the use of computerized clinical reminders and patient education. CONCLUSION: Clinicians frequently do not follow recommended guidelines for the management of GIOP. Improving the management of GIOP will likely require a fundamental redesigning of care processes for this disorder in order to overcome provider, patient-related, and system barriers.     

Barriers in the management of glucocorticoid‐induced osteoporosis

Objective

To determine present practice for the management of glucocorticoid‐induced osteoporosis (GIOP) in veterans; to characterize provider knowledge, beliefs, and practice behaviors regarding management of GIOP; and to identify potential barriers and interventions in the management of GIOP.

Methods

To characterize current management of GIOP in an academic veterans administration medical center, we conducted a retrospective chart review of 100 patients who were prescribed a 90‐day supply of prednisone. To assess clinicians' knowledge of GIOP clinical guidelines and perceptions of GIOP management, primary care clinicians and subspecialists completed a questionnaire and participated in focus groups.

Results

Chart review revealed that only 32 of 100 patients receiving long‐term glucocorticoid treatment underwent bone mineral density testing, and only 32 patients were prescribed the recommended calcium supplements. Of the 23 providers who completed the questionnaire and participated in the focus groups, 4 correctly identified both the dose and duration of glucocorticoid use at which GIOP prevention measures should be instituted. Common GIOP management barriers cited by participants were lack of knowledge, having limited time during the clinic visit to address all problems, patient nonadherence, and system problems. The most commonly mentioned potential interventions were the use of computerized clinical reminders and patient education.

Conclusion

Clinicians frequently do not follow recommended guidelines for the management of GIOP. Improving the management of GIOP will likely require a fundamental redesigning of care processes for this disorder in order to overcome provider, patient‐related, and system barriers.     

Update on glucocorticoid-induced osteoporosis

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, and fractures are the most frequent adverse effects of this medication. Glucocorticoids have several direct and indirect adverse effects on bone, primarily through reduction in osteoblasts and osteocyte activity, and life span. Recent advances in the pathophysiology and prevention of this complication of therapy provide hope for its amelioration in patients being treated with glucocorticoids. Several effective pharmacologic agents are now available, and guidelines for the prevention and treatment of GIOP have been published. Despite these advances, many patients still do not receive proper prevention or therapy.     

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.     

Glucocorticoid-induced osteoporosis: recent findings

The clinical features, pathogenesis and management of bone involvement in Cushing's syndrome are briefly reviewed. Personal data on bone mineral density and markers of bone turnover in Cushing's syndrome and adrenal incidentalomas are also reported. As long ago as 1932, Harvey Cushing recognized osteoporosis as a serious consequence of endogenous hypercortisolism. The introduction of cortisone in the therapy of autoimmune, rheumatic, allergic or dermatologic disorders was followed by several reports of detrimental effects on bone of patients who had undergone prolonged glucocorticoid treatment. Due to the rarity of Cushing's syndrome, most of the studies in the literature on glucocorticoid-induced osteoporosis refer to exogenous over-exposure to cortisone and its synthetic derivatives. Only a small number of works concern endogenous hypercortisolism, even if the characteristics of bone damage seem qualitatively the same. Finally, very few data are reported on the hypothetical detrimental effect on bone in the condition of the silent hypercortisolism of adrenal incidentalomas. Glucocorticoid-induced osteoporosis in Cushing's syndrome often results in vertebral fractures, and bone loss is more evident in trabecular than in cortical bone. Notwithstanding some distinctive features in osteoporosis induced by endogenous and exogenous glucocorticoid excess, the common eventual picture is notable bone damage that involves mainly the trabecular bone. Prompt and effective therapy is mandatory to reduce the risk of fractures. The present options include calcium and vitamin D supplementation, estrogen replacement therapy, bisphosphonates, either oral or parenteral. A novel approach to the clinical problem of glucocorticoid-induced osteoporosis might, in the future, be based on studies on selective glucocorticoid receptor modulators, a new class of synthetic glucocorticoids that exhibit significant anti-inflammatory and immunosuppressive activities, with reduced side effects on bone.     

Glucocorticoid-induced osteoporosis: mechanisms for bone loss; evaluation of strategies for prevention

Osteoporosis is a common complication of chronic glucocorticoid therapy, especially in older patients who already are at risk of having a reduced bone mass. Glucocorticoids cause bone loss by altering the bone remodeling sequence: bone resorption by osteoclasts is increased, and bone formation by osteoblasts is decreased. Serum levels of osteocalcin, a protein made by osteoblasts, are decreased with glucocorticoid therapy, further evidence of decreased osteoblast function. Glucocorticoids decrease calcium absorption by the gastrointestinal tract and increase renal calcium excretion. Several recent studies suggest that low-dose glucocorticoid therapy is not associated with bone loss. Calcium supplementation with vitamin D is recommended. Several short-term studies have shown prevention of glucocorticoid-induced bone loss with bisphosphonates, calcitonin, and progesterone. Long-term clinical trials should be undertaken to determine strategies to prevent this type of osteoporosis.     

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.     

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.     

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.     

Risk factors for osteoporosis in female patients with systemic lupus erythematosus

In the last years it has been recognized that patients with systemic lupus erythematosus (SLE) are at high risk of osteoporosis (OP) and fractures, both occurring through disease-specific (chronic arthritis, reduced physical activity, induction of cytokines promoting bone resorption, renal impairment, endocrine factors) and nondisease-specific mechanisms (sunshine avoidance with consequent vitamin D deficiency, glucocorticoids, immunosuppressants and chronic anticoagulants). Regarding anticoagulants, subcutaneous heparin is crucial against the risk of recurrent thromboembolism or pregnancy loss, specifically in patients with SLE and anti-phospholipid syndrome (APS). Thus heparin-induced OP represents one of the hazards of this treatment, first because heparin must be used long-term and secondly because pregnancy and lactation themselves may predispose to OP and fractures. Current data suggest the use of prophylaxis with calcium and vitamin D in all patients treated with heparin during pregnancy. Nevertheless glucocorticoid-induced OP (GIOP) is considered the most serious risk factor for OP and fractures in SLE patients. All guidelines recommend general measures and supplementation with calcium and vitamin D in all patients. However when considering premenopausal patients, there is no generally recommended treatment. Bisphosphonates, which are considered the first choice therapy for the prevention and treatment of GIOP, should be used 'cautiously' in these patients. Therefore the potential risks and lack of efficacy data on fracture risk reduction in premenopausal patients must be weighed against their proven efficacy in postmenopausal patients.