Biomedicine & Pharmacotherapy 58 (2004) 500504 http://france.elsevier.

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Dossier : Osteoporosis

Glucocorticoid-induced osteoporosis
Yasuhiro Tamura a,*, Hiroko Okinaga b, Hiroshi Takami c
a

Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-Ku, Tokyo 173-8605, Japan b Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-8655, Japan c Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-Ku, Tokyo 173-8605, Japan Received 30 March 2004 Available online 11 September 2004

Abstract Glucocorticoids are important drugs in the treatment of variety diseases, but long-term period use can lead to various adverse effects, including osteoporosis. Glucocorticoid-induced osteoporosis is mainly caused by inhibition of osteoblastic bone formation, which results not only in decreased bone mineral density, but reduction of bone strength by trabecular thinning in bone microstructures. The evidence suggests that daily oral glucocorticoid doses higher than 5 mg prednisolone or equivalent increase the risk of fracture within 36 months after the start of therapy. High-dose inhaled glucocorticoids may also increase fracture risk. The diagnostic procedures are similar to those for primary osteoporosis, but the diagnostic threshold for bone mineral density needs to be higher than that for primary osteoporosis. Treatment with vitamin D, calcitonin, sex hormone replacement, and bisphosphonates has been shown to be effective, and bisphosphonates have been demonstrated to be the most valuable drugs for glucocorticoid-induced osteoporosis. There are several lines of evidence indicating that they are effective in preventing and treating low bone mineral density and in reducing fracture risk. 2004 Elsevier SAS. All rights reserved.
Keywords: Glucocorticoids; Osteoporosis; Fracture

1. Introduction Glucocorticoids are widely used to treat a variety of diseases, including collagen diseases, bronchial asthma and skin diseases. Because of improvements in the outcome of these diseases, the long-term side effects of glucocorticoids, including osteoporosis, have become an important problem. Osteoporosis not only causes pain in the form of fractures but may increase susceptibility to complications, such as pneumonia. Osteoporosis is classied into primary and secondary one, and glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis. 2. Pathogenesis Bone formation by osteoblasts and bone resorption by osteoclasts continuously occur in bone tissue. Bone forma* Corresponding author. E-mail address: tamu@kt.rim.or.jp (Y. Tamura). 0753-3322/$ - see front matter 2004 Elsevier SAS. All rights reserved. doi:10.1016/j.biopha.2004.08.018

tion and resorption are usually balanced, and osteoporosis occurs when bone mass and quality are reduced by an excess of bone resorption over bone formation. Glucocorticoid-induced osteoporosis is characterized by decreased bone formation, and its pathogenesis is probably different from that of postmenopausal osteoporosis, because postmenopausal osteoporosis is mainly caused by increased bone resorption. 2.1. Effect on bone formation Glucocorticoids seem to cause bone loss primarily by suppressing osteoblastic functions and histomorphometric studies have generally indicated a reduction of bone formation [1,10,15]. Glucocorticoids also reduced serum markers of bone formation, such as osteocalcin [29,34,35,37,39] and PICP (procollagen type I carboxy-propeptide) [30,35]. Cell biology studies have suggested that glucocorticoids inhibit osteoblastic proliferation and function. For example, glucocorticoids appear to inhibit production of bone matrix components, such as type I collagen, by osteoblasts [17],

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increase osteoblastic and osteocytic apoptosis [21,38,50], decrease expression of Runx2/Cbfa1 and tumor growth factor b(TGF-b) type 1 receptor [9], increase peroxisome proliferator-activated receptor-c2(PPARc2) expression [43], and modulate insulin-like growth factor (IGF) [16] and IGFbinding protein. Runx2/Cbfa1 is a transcriptional factor that is essential to osteoblastic differentiation. TGF-b and IGF are local factors that are important for bone formation, and PPARc2 is an important transcriptional factor for differentiation from bone marrow mesenchymal cells to adipocytes, not to osteoblasts. 2.2. Effect on bone resorption There is controversy as to whether glucocorticoids increase bone resorption. Some histomorphometric studies have indicated increases in bone resorption [1,44], but the changes in bone resorption markers in serum and urine have not been consistent [29,37,39]. Systemic and local factors have been proposed for the effects of glucocorticoid on bone resorption, and systemic effects mediated by parathyroid hormone and sex hormones have been identied. Glucocorticoids decrease intestinal calcium absorption [22,33] and increase renal calcium excretion [19], and the secondary hyperparathyroidism caused by the negative calcium balance may increase osteoclastic activity and decrease bone mass. Some reports, however, have indicated that glucocorticoid therapy may not increase parathyroid hormone levels [36,37]. Glucocorticoids may cause hypogonadism by inhibiting gonadotropin secretion and inhibiting dehydroepiandrosterone sulfate (DHEA-S) secretion via adrenocorticotropic hormone (ACTH) suppression, and the decrease of sex hormone levels may increase bone resorption and decrease bone mass. In terms of local effects, glucocorticoids may directly promote osteoclastogenesis by increasing receptor activator of NF-jB ligand (RANK-L) and colony-stimulating factor-1 (CSF-1) and decreasing osteoprotegerin [8]. RANK-L is a molecule that stimulates osteoclast generation and differentiation, whereas osteoprotegerin is a decoy receptor of RANK-L and inhibits osteoclast generation and differentiation. CSF-1 stimulates osteoclastic differentiation. Glucocorticoids may also increase the number of osteoclasts by inhibiting osteoclast apoptosis [49]. But glucocorticoids may decrease bone resorption through reduction in expression of collagenase and increase of osteoclastic apoptosis [8].

bral fractures of 2.60 (2.312.92). The relative risk of hip fractures and vertebral fractures at higher doses (prednisolone >7.5 mg/day or equivalent) was 2.27 and 5.18, respectively, whereas at lower doses (prednisolone <2.5 mg/day or equivalent) the risk was only 1.17 and 1.55, respectively. It was concluded that oral glucocorticoid therapy at dose of 5 mg of prednisolone (or equivalent) daily increases the risk of fractures, but that even in low-dose oral glucocorticoid therapy does not eliminate the increased fracture risk. Fracture risk increased rapidly within the rst 36 months after the start of glucocorticoid therapy [48]. Oral glucocorticoid therapy decreases bone mineral density, a major indicator of bone fragility in osteoporosis, and the decrease is rapid in the rst months after the start of therapy but slows after about 1 year [48]. However, even in chronic glucocorticoid therapy the rate of bone loss may be 23 times greater than in non-users of glucocorticoids [42]. Strong correlations have been found between the cumulative dose and loss of bone mineral density [48]. Oral glucocorticoids affect not only bone mass but bone structure. At similar BMD levels, postmenopausal women taking glucocorticoids had considerably higher rates of fracture than non-users [45]. Glucocorticoids may affect bone strength by thinning the trabeculae [1,44].

4. Inhaled glucocorticoids and osteoporosis Inhaled glucocorticoids are one of the most important forms of drug therapy for asthma and chronic obstructive pulmonary disease. There is controversy as to whether inhaled glucocorticoids cause bone loss or increase the risk of fractures. Many studies have indicated that they may cause bone loss [20,25,32,51]. A large population-based casecontrol study indicated a dose-dependent increase in risk of hip fracture in association with exposure to inhaled glucocorticoids [24], but it is difcult to demonstrate whether bone loss and fractures are attributable to inhaled glucocorticoids, because bone loss and fractures occurring as a result of the pulmonary disease itself are confounding factors. A recent systematic review concluded that there is no evidence that conventional doses of inhaled glucocorticoids for 2 or 3 years affect BMD or risk of vertebral fractures [26]. However, in the studies that met the criteria for this review, low and medium doses were used in patients at low risk for osteoporosis. Higher doses of inhaled glucocorticoids may cause bone loss and fractures in high-risk patients, for example, postmenopausal women. Further investigations are needed in regard to this issue.

3. Oral glucocorticoids and osteoporosis Oral glucocorticoids increase fracture risk in a dosedependent manner. The results of a large retrospective cohort study [46,47] have indicated a relative risk of nonvertebral fractures during oral glucocorticoid treatment of 1.33 (95% condence interval, 1.291.38), and a relative risk of verte5. Diagnosis The diagnostic procedures for glucocorticoid-induced osteoporosis are almost the same as for primary osteoporosis. Bone mineral density is usually evaluated by dual photon

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X-ray absorptiometry (DXA) of lumbar spine or the femoral neck. Bone resorption markers and bone formation markers can be used to evaluate bone turnover. Osteoporosis or bone diseases due to other causes should be ruled out. Old vertebral fractures and clinical risk factors for osteoporosis, such as age, smoking, alcohol, menstrual status, family history, should also be evaluated. The bone mineral density threshold for the diagnosis of glucocorticoid-induced osteoporosis has yet to be dened. The fracture thresholds in primary and glucocorticoidinduced osteoporosis seem to be different [11,45]. A recent review stated that the fracture threshold for bone mineral density of the lumbar spine was found to be a T score of 1.2 in a glucocorticoid-induced osteoporosis study and 2.4 to 2.8 in postmenopausal osteoporosis studies [11] (T score = [bone mineral density of the patient mean bone mineral density of young adults]/standard deviation of bone mineral density of young adults). The fracture threshold may differ according to the diseases that require glucocorticoid therapy, and this is an issue that should be investigated in the future. The recommended diagnostic threshold of bone mineral density for glucocorticoid-induced osteoporosis differs in several countries. The diagnostic threshold for primary osteoporosis in most countries is a T score of 2.5. The UK consensus group recommends a T score of 1.5 as the threshold for glucocorticoid-induced osteoporosis [18] and, the American College of Rheumatology recommends 1.0 [5]. 6. Drug therapy Vitamin D, vitamin D metabolites, hormone replacement therapy, calcitonin, PTH, and bisphosphonates are known to be effective for the treatment of glucocorticoid-induced osteoporosis, and bisphosphonates have become the most valuable drugs, because of strong evidence that they increase bone mineral density and decrease fracture risk. 6.1. Bisphosphonates Bisphosphonates are pyrophosphate analogues that readily bind to bone minerals, and they reduce bone resorption by inhibiting osteoclasts and increase bone mass. Bisphosphonates have been demonstrated to be effective in the treatment of primary osteoporosis. The rst generation drug, etidronate, and new generation drugs, alendronate and risedronate, are now available for treatment. There is evidence that bisphosphonates both increase bone mineral density and reduce fracture risk. Most other drugs have been shown to increase bone mineral density alone, with no evidence that they reduce fracture risk. Bisphosphonates have also been shown to prevent rapid loss of bone mineral density in patients started on glucocorticoid therapy and to increase bone mineral density after long-term glucocorticoid therapy. A randomized controlled study of the preventive effect of bisphosphonates in 224 men and women started on glucocor-

ticoid therapy (prednisolone 7.5 mg/day or equivalent) and expected to continue glucocorticoids for another 12 months showed that at the end of 12 months risedronate 5 mg/day had prevented loss of bone mineral density in the lumbar spine, femoral neck, and femoral trochanter, and tended to decrease new vertebral fractures [12]. Another randomized controlled study of 290 men and women on glucocorticoid therapy (prednisolone 7.5 mg/day or equivalent) for 6 months or more showed that risedronate increased bone mineral density in the lumbar supine, femoral neck, and femoral trochanter, and signicantly reduced vertebral fractures by 70% [40]. Alendronate and etidronate have also been shown to be effective for the treatment and prevention of glucocorticoidinduced osteoporosis and to decrease the risk of vertebral fractures [3,4]. A comparative analysis revealed that bisphosphonates were more effective against glucocorticoid-induced osteoporosis than calcitonin, vitamin D, and calcium [7]. 6.2. Vitamin D A meta-analysis showed that vitamin D therapy was effective against glucocorticoid-induced osteoporosis, but that it was less effective than bisphosphonates [6,7]. Bisphosphonates were more effective when used in combination with vitamin D than when used alone [7]. 6.3. Estrogen replacement therapy Although estrogen replacement therapy is an established treatment for postmenopausal osteoporosis, there are few data showing its effects on glucocorticoid-induced osteoporosis. Controlled trials have shown that estrogen replacement therapy increases lumbar spine bone mass in postmenopausal women using low dose glucocorticoid [23,31]. 6.4. Calcitonin A recent review indicated that calcitonin therapy increases the bone mineral density of the lumbar spine in glucocorticoid-induced osteoporosis [13]. 6.5. Other drugs Parathyroid hormone increases the lumbar and hip bone mineral density of postmenopausal women on estrogen replacement therapy [27,28], and testosterone increases lumbar bone mineral density in men on glucocorticoids [14,41].

7. Managements Several guidelines for glucocorticoid-induced osteoporosis have been proposed, based on the above ndings [2,5,18]. The guidelines are applied to patients who are taking or expected to take oral glucocorticoid for 36 months.

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First, life-style should be modied. Patients should be encouraged to stop smoking, to do weight-bearing exercises and to reduce alcohol consumption, if excessive. Calcium and vitamin D supplementation should be started, if there are no contraindications. If the patient has hypogonadism, hormone replacement should be considered. The protocol in the guideline of American College of Rheumatology (ACR) [5] is divided into primary prevention and secondary prevention. It recommends that patients starting glucocorticoid therapy (prednisolone 5 mg/day or equivalent) planned for 3 months should be prescribed a bisphosphonate. A bisphosphonate is also recommended for patients already on long-term glucocorticoid therapy (prednisolone 5 mg/day or equivalent), if their bone mineral density is below a T score of 1. The guideline of UK Consensus Group [18] recommends drug therapy for the patients with strong risk factors for osteoporosis. If not, it recommends drug therapies when bone mineral density is below a T score of 1.5. The latest version of UK guideline (http://www.eguidelines.co.uk) does not distinguish between doses of glucocorticoid, because low-dose of glucocorticoids may increase fracture risk.

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