- Email: [email protected]
Management of glucocorticoid-induced osteoporosis: Lessons for clinical practice
Joint Bone Spine 78 (2011) S222-S226
Supplement
Joint Bone Spine
2nd National ODISSEE Meetings (Osteoporosis: DIagnosis and Surveillance of SEvErity)
Male osteoporosis & cortisonical osteoporosis
xxxxx
Issue produced with the institutional support of Lilly Inc.
December 2011 Vol. 79 – Supplement 2 p. S189-S226 ISSN 1297-319X
Editorial
Management of glucocorticoid-induced osteoporosis: lessons for clinical practice Christian Rouxa,*, Gérald Rajzbaumb, Gauthier Morelc, Erick Legrandd, Michel Larochee, Emmanuel Hoppéd, Florence Chopinf, Séverine Borge, Emmanuel Biverg, Bernard Cortetg, Thierry Thomasf aUniversité
Paris-Descartes, service de rhumatologie B, hôpital Cochin, 27 rue du faubourg Saint-Jacques, 75014 Paris, France de rhumatologie, groupe hospitalier Paris Saint-Joseph, 185 rue Raymond Losserand, 75674 Paris cedex 14, France cService de rhumatologie, centre hospitalier, avenue Desandrouins, BP 479, 59322 Valenciennes cedex, France dUniversité d’Angers, service de rhumatologie, CHU Angers, 4 rue Larrey, 49033 Angers cedex 01, France eService de rhumatologie, hôpital Purpan, 1 place du docteur Baylac, 31059 Toulouse, France fINSERM U1059, service de rhumatologie, CHU Bellevue, 25 boulevard Pasteur, 42055 Saint-Étienne, France gDépartement universitaire de rhumatologie, hôpital Roger Salengro, rue du Professeur Emile Laine, 59037 Lille cedex, France bService
Keywords: Glucocorticoids Fractures Osteoporosis Bone densitometry Treatment
Glucocorticoid-induced osteoporosis, the leading cause of secondary osteoporosis, results from the well-documented deleterious effects of glucocorticoids on bone [1, 2]. The prevalence of chronic glucocorticoid use is nearly 1% in the general population and up to 2.5% in individuals aged 70 to 80 years [3]. The main reasons for glucocorticoid therapy are inflammatory joint diseases and lung diseases [3, 4]. In everyday practice, glucocorticoidinduced osteoporosis is underdiagnosed and undertreated [5, 6]. Gradual improvements in diagnostic tools, together with the introduction of drugs that either diminish the need for high-dose glucocorticoid therapy or treat glucocorticoid-induced osteoporosis, can be expected to improve the management of this disorder. Following on the first national ODISSEE (Osteoporosis DIagnosis and Surveillance of SEvErity) meeting [7], the second national ODISSEE meeting held in 2010 convened a panel of national experts to exchange viewpoints on glucocorticoidinduced osteoporosis, based on a literature review conducted by the scientific committee. The experts focused on three main issues and the content of their discussions is reviewed herein.
1.
Are glucocorticoids really deleterious for bone?
Glucocorticoids have dose-dependent toxic effects on bone that are related to both direct and indirect mechanisms, and an increase in the fracture risk was seen even with low glucocorticoid dosages. Therefore, there is a recommendation to give osteoporosis medications (e.g., teriparatide or bisphosphonates) to patients who are starting or continuing long-term oral glucocorticoid therapy. Glucocorticoid therapy is effective in combatting inflammation in patients with chronic inflammatory joint disease. This effect influences the risk/benefit ratio of glucocorticoid therapy in terms of the fracture risk in patients with chronic inflammation. Although glucocorticoid therapy has been reported to increase the fracture risk in patients with rheumatoid arthritis (RA) [8], this finding should be put in balance with a number of other observations: • among patients with early polyarthritis, those whose C-reactive protein levels remain elevated during follow-up experience rapid bone loss [9];
* Corresponding author. E-mail address: [email protected] (Christian Roux). © 2011 Société française de rhumatologie. Published by Elsevier masson SAS. All rights reserved.
C. Roux et al. / Joint Bone Spine 78 (2011) S222-S226
• RA (without glucocorticoid therapy) is an independent risk factor for osteoporosis [9]; • among patients receiving aggressive treatments for recentonset RA (BeSt study), those receiving high-dose glucocorticoid therapy do not experience a faster rate of bone loss [10]; • and in patients with active RA given TNFα antagonist therapy combined with a stable methotrexate dosage and, if needed, less than 10 mg/d of prednisone, bone loss correlated initially with disease activity and disease duration but stopped after the introduction of the TNFα antagonist. The change in bone loss correlated negatively with the change in CRP. Furthermore, combination therapy with a glucocorticoid and a TNFα antagonist was associated with an increase in BMD values at the proximal femur [11]. These clinical data do not call into question the deleterious effects of glucocorticoids on bone, most notably in older individuals. However, they indicate that inflammation is also a major risk factor for bone loss, as now clearly demonstrated by pathophysiological and clinical data [12].
In practice When highly effective disease-modifying treatment is available, as is now the case in RA, oral low-dose glucocorticoid therapy to improve the control of the inflammatory process may exert beneficial effects on bone. These data are not relevant to other diseases (e.g., giant cell arteritis, respiratory diseases, and gastrointestinal diseases).
estimated at 1.33 for peripheral fractures, 1.61 for proximal femoral fractures, and 2.6 for vertebral fractures [15]. The risk increase occurred within the first 6 months of treatment.
In practice The rapid occurrence of bone loss and early fracture risk increase associated with glucocorticoid therapy warrant an early assessment of the appropriateness of osteoporosis treatment at the initiation of oral glucocorticoid therapy that is expected to be prolonged, particularly when the daily dosage is high.
2.2. Who should be treated? 2.2.1.
2.
Glucocorticoid-induced osteoporosis; when and who should we treat?
Glucocorticoid therapy induces an early phase of rapid bone loss, which is measurable after only a few months, followed by prolonged slower bone loss at a slower pace. Several recommendations about the management of glucocorticoidinduced osteoporosis have been issued, including 2003 French recommendations for oral dosages 7.5 mg/d, in which the threshold for treatment is a BMD T-score -1.5 SD [13]. More recently, the American College of Rheumatology (ACR) issued recommendations based on the FRAX tool [14]. Nevertheless, a number of specific situations continue to raise challenges, most notably the use of low daily dosages in young individuals or men.
2.1. When should treatment be started? In the General Practice Research Database in the UK, the relative risk of fractures in glucocorticoid-treated patients was
Selection based on the T-score
A dissociation has been reported between the BMD values and the fracture risk: thus the fracture risk is increased even when the decrease in BMD values versus baseline is small [16, 17]. The fracture risk increase during glucocorticoid therapy has been described as independent from BMD by some authors [18]. However, a T-score < -1.5 seems relevant for the management of the fracture risk in glucocorticoid-treated patients [19].
2.2.2. These hypotheses deserve to be evaluated in patients with RA in order to answer the following questions: Should complete glucocorticoid withdrawal be included among the goals of biologic therapy? and Should bisphosphonate therapy be continued in patients who achieve a complete remission of RA with combined disease-modifying and glucocorticoid therapy?
S223
Selection based on the glucocorticoid dosage:
• Effect on bone loss: published data on whether there is a threshold dose above which adverse bone effects occur are conflicting [20]. However, a dose of 7.5 mg/d was associated with a decrease in lumbar-spine BMD values [21, 22]. • Effect on the fracture incidence: the daily glucocorticoid dosage predicted the fracture risk, starting with the lowest dosages, i.e., <2.5 mg/d [15], in large cohorts (for which no information was given on concomitant treatments).
2.2.3.
Selection based on other risk factors
The fracture risk increase associated with glucocorticoid therapy varies little with age or sex. In contrast, the fracture incidence increases with age in glucocorticoid-treated patients. These data indicate a need for evaluating the absolute fracture risk in glucocorticoid-treated patients. There are two available risk scores, the Van Staa score [23] and the FRAX score [24]. The value of the FRAX score is limited by the binary nature of the glucocorticoid-therapy item, which takes neither the dosage nor the duration of glucocorticoid therapy into account.
In practice Although the fracture risk remains difficult to predict, the treatment decision in the individual patient should rely on a number of factor including age, menopausal status, BMD values, and the glucocorticoid dosage.
S224
3.
C. Roux et al. / Joint Bone Spine 78 (2011) S222-S226
Selecting the optimal treatment for glucocorticoid-induced osteoporosis
At glucocorticoid therapy initiation, the individual fracture risk should be evaluated. In particular, prevalent vertebral fractures should be sought, the risk profile established, and the menopausal status specified. This evaluation will guide treatment decisions about the use of medications in addition to general measures and vitamin D supplementation.
In practice Selection of a bisphosphonate relies on a discussion between the rheumatologist and patient after information about the treatment modalities and comparative safety profiles. The experts suggest giving preference to oral bisphosphonates in young patients and to intravenous bisphosphonates in patients on multiple medications and in patients with gastrointestinal contraindications to oral administration, expected poor treatment adherence, or high-dose glucocorticoid therapy.
3.1. Treatment modalities 3.1.1.
Role for vitamin D and calcium supplementation
Calcium and vitamin D deficiencies are common. In practice The experts recommend routine vitamin D supplementation. Patients whose food frequency questionnaire indicates an inadequate dietary calcium intake should receive supplemental calcium.
3.1.2.
Role for oral or parenteral bisphosphonate therapy
In France, three oral bisphosphonates (etidronate 400 mg, alendronate 5 mg, and risedronate 5 mg) are licensed for use in preventing bone loss in patients requiring glucocorticoid therapy in a dosage 7.5 mg/d prednisone-equivalent for at least 3 months. For risedronate, the license applies only to postmenopausal women. A single intravenous bisphosphonate (zoledronic acid 5 mg/year) is licensed for use in postmenopausal women and in men at high fracture risk (Table 1) [25]. Bisphosphonates improve BMD values at the lumbar spine when used to prevent or reverse GIO. The impact on femoral BMD values varies across bisphosphonates, and the fracture risk decrease is greatest in older women having low baseline BMD values at the lumbar spine.
3.1.3.
Role for teriparatide
In France, teriparatide is licensed for use in glucocorticoidinduced osteoporosis in women and men at high fracture risk receiving long-term glucocorticoid therapy. The license was granted based on a double-blind randomized trial in 428 patients with glucocorticoid-induced osteoporosis who received either alendronate 10 mg/d (n=214) or teriparatide 20 μg/d (n=214). The change in lumbar-spine BMD was significantly greater in the teriparatide group starting at the sixth treatment month. At follow-up completion, the lumbar-spine BMD increase was +7.2%±0.7% with teriparatide and +3.4%±0.7% with alendronate (P<0.001 between the two groups) [26].
In practice Teriparatide is indicated in women and men of any age who are at high fracture risk. The marketing license limits the treatment duration to 24 months, and the first 18 months are reimbursed by the French public healthcare insurance system provided the patient has at least two prevalent vertebral fractures. Consequently, imaging studies should be obtained routinely to assess the presence of prevalent vertebral fractures.
Table 1 Medications licensed for use in glucocorticoid-induced osteoporosis. NPN (brand name) Alendronate
(Fosamax®
Marketing license 5 mg)*
Treatment of osteoporosis: Prevention of bone loss in patients requiring systemic glucocorticoid therapy for longer than 3 months in a daily dosage greater than 7.5 mg of prednisone-equivalent
Etidronate (Didronel® 400 mg)**
Treatment of osteoporosis: Prevention of bone loss in patients requiring systemic glucocorticoid therapy for longer than 3 months in a daily dosage greater than 7.5 mg of prednisone-equivalent
Risedronate (Actonel® 5 mg)
Maintaining or increasing bone mass in postmenopausal women requiring long-term systemic glucocorticoid therapy (for longer than 3 months) in daily doses of at least 7.5 mg prednisone-equivalent
Zoledronic acid 5 mg/year (Aclasta® 5 mg)
Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy (>7.5 mg/d oral prednisone (or equivalent)): • in postmenopausal women • in men at high fracture risk
Teriparatide (Forsteo®)
Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy (equivalent to 5 mg or greater of prednisone for at least 3 months) in women and in men at high fracture risk
* Not available in France ** This drug is not recommended by French health authorities, as the efficacy of DIDRONEL 400 mg in preventing peripheral fractures, most notably at the femoral neck, remains unproven [25].
C. Roux et al. / Joint Bone Spine 78 (2011) S222-S226
3.1.4.
Treatment sequence
In practice • After 18 months of teriparatide therapy, the experts recommend bisphosphonate therapy for as long as the glucocorticoid is required. • After failure of a bisphosphonate, defined as significant bone loss or a new fracture, teriparatide therapy may be considered, according to the limits set by the marketing license and French public healthcare insurance system. • Treatment duration: the available studies didn’t determine the optimal treatment duration. In treatment trials of bisphosphonates and teriparatide, BMD values were obtained only during the first 3 years.
S225
Substantial contributions and financial support for research projects or as an investigator in studies sponsored by Amgen, Lilly, MSD, Novartis, Roche. Th. Thomas: Clinicial trials: as main (head) clinical or laboratory investigator, or study coordinator (Ipsen) and as coinvestigator or study contributor (Amgen, Lilly, MSD, Novartis, Servier, Warner-Chilcott); Occasional involvements: expert reports (Warner-Chilcott) and advisory services (Amgen, Lilly, Novartis, Servier, Warner-Chilcott); Conferences: attendance as contributor (Amgen, BMS, Chugai, GSK, Ipsen, Lilly, MSD, Novartis, Roche, Servier, Warner-Chilcott); Substantial contributions to the finances of a company or organisation which he is responsible (Amgen, BMS, Chugai, MSD, Novartis, Roche). This special issue was realized as part of 2nd National Meetings ODISSEE organized with the institutional support of laboratories Lilly Inc.
3.1.5.
Strategy at glucocorticoid therapy discontinuation
References In practice At discontinuation of long-term glucocorticoid therapy, the experts recommend a repeat evaluation of the fracture risk. If the risk remains high, most notably in postmenopausal women, the osteoporosis medication should be continued. In contrast, if stopping the glucocorticoid, together with the good disease control this event usually signifies, results in a low fracture risk, the osteoporosis medication can be stopped at the same time as the glucocorticoid.
Disclosures Ch. Roux received research grants and/or honoraria from Amgen, MSD, Servier, Lilly, Novartis. G. Rajzbaum: Clinical trials: as co-investigator or study contributor (Lilly, Pfizer); Occasional involvements: expert reports (Lilly, Amgen); Conferences: attendance as contributor (Lilly, Amgen, Ipsen). G. Morel: Conferences: attendance as contributor (Lilly, MSD, Roche). E. Legrand, E. Hoppé, S. Borg: no conflicts of interests. M. Laroche: Clinical trials: as main (head) clinical or laboratory investigator, or study coordinator (Lilly, Amgen, Roche, Servier, Procter & Gamble); Occasional involvements: experts reports and advisory services (Amgen, Lilly, MSD, Roche, Servier, Pierre-Fabre, Procter & Gamble, WC Pharmaceuticals, Daichi Sankio, Novartis); Conferences: attendance as contributor and as audience member (Amgen, Lilly, MSD, Roche, Servier, PierreFabre, Procter & Gamble, WC Pharmaceuticals, Daichi Sankio, Novartis); Substantial contributions to the finances of a company or organisation which he is responsible (Novartis, MSD, Amgen). F. Chopin: Clinical trials: as co-investigator or study contributor (MSD, Roche, Pfizer, Lilly). E. Biver: Conferences: attendance as contributor (Amgen, Lilly) and as audience member (Amgen, Lilly, Servier). B. Cortet: Occasional involvements: expert reports and advisory services (Amgen, Daiichi-Sankyo, Ferring, Lilly, MSD, Medtronic, Novartis, Roche, Servier, Warner & Chilcott) ;
[1] Orcel P. Prevention and treatment of glucocorticoid-induced osteoporosis in 2005. Joint Bone Spine 2005;72:461-5. [2] Briot K, Cortet B, Trémollières F, et al. Male osteoporosis: diagnosis and fracture risk evaluation. Joint Bone Spine 2009;76:129-33. [3] Van Staa TP, Leufkens HG, Abenhaim L, et al. Use of oral corticosteroids in the United Kingdom. QJM 2000;93:105-11. [4] Walsh LJ, Wong CA, Pringle M, et al. Use of oral corticosteroids in the community and the prevention of secondary osteoporosis: a cross sectional study. Br Med J 1996;313:344-6. [5] Curtis JR, Westfall AO, Allison JJ, et al. longitudinal patterns in the prevention of osteoporosis in glucocorticoids treated patients. Arthritis Rheum 2005;52:2485-94. [6] Lespessailles E, Cotté FE, Roux C, et al. Prevalence and features of osteoporosis in the French general population: The Instant study. Joint Bone Spine 2009;76:394-400. [7] Roux C, Confavreux CB, Cortet B, et al. Severe osteoporosis: diagnosis and follow-up. Lessons for clinical practice. Joint Bone Spine 2010;77:S139-41. [8] Laan RFJ, van Riel LCM, van de Putte LBA, et al. Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis. Ann Intern Med 1993;119:963-8. [9] Gough AK, Lilley J, Eyre S, et al. Generalised bone loss in patients with early rheumatoid arthritis. Lancet 1994;344:23-7. [10] Güler-Yüksel M, Allaart CF, Goekoop-Ruiterman YPM, et al. Changes in hand and generalised bone mineral density in patients with recent-onset rheumatoid arthritis. Ann Rheum Dis 2009;68:330-6. [11] Wijbrandts CA, Klaasen R, Dijkgraaf MGW, et al. Bone mineral density in rheumatoid arthritis patients 1 year after adalimumab therapy: arrest of bone loss. Ann Rheum Dis 2009;68:373-6. [12] Ghazi M, Kolta S, Briot K, et al. Prevalence of vertebral fractures in patients with rheumatoid arthritis: revisiting the role of glucocorticoids. Osteoporos Int 2011;25 [Epup ahead of print] [13] Agence Française de Sécurité Sanitaire des Produits de Santé. Recommandation de bonne pratique. Traitement médicamenteux de l’ostéoporose cortisonique. Argumentaire. Edition de février 2003. [14] Grossman JM, Gordon R, Ranganath VK, et al. American college of rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2010;62:1515-26. [15] Van Staa TP, Leufkens HG, Abenhaim L, et al. Use of oral corticosteroids and risk of Fractures. J Bone Min Res 2000;15:993-1000.
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[16] Roux C, Orcel P. Steroid induced osteoporosis: prevention and treatment. Rev Med Int 2003;24:384-8. [17] Orcel P. Management of corticoid-induced osteoporosis. Presse Med 2006;35:1571-7. [18] Laan RF, Van Riel PL, Van de Putte LB, et al. Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis. A randomized controlled study. Ann Intern Med 1993;119:963-8. [19] Mc Kenzie R, Reynolds JC, O’Fallon A, et al. Decreased bone mineral density during low dose glucocorticoid administration in a randomised-placebo controlled trial. J Rheumatol 2000;27:2222-5. [20] Van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis : a Meta-analysis. Osteoporos Int 2002;13:777-87. [21] Kanis JA, Johansson H, Oden A, et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 2004;19:893-9.
[22] Selby PL, Hasley JP, Adams KRH, et al. Corticosteroid Do Not Alter the Threshold for Vertebral Fracture. J Bone Min Res 2000;15:952-6. [23] Van Staa TP, Geusens P, Pols HA, et al. A simple score for estimating the long-term risk of fracture in patients using oral corticoids. QJM 2005;98:191-8. [24] Kanis J.A, Johnell O, Oden A, et al. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int 2008;19:385-97. [25] Synthèse d’avis de la commission de la transparence. DIDRONEL (acide étidronique), bisphosphonate – Synthèse d’avis Rhumatologie - Mise au point. Décembre 2010. Avis défavorable au remboursement en raison d’un intérêt clinique insuffisant. [26] Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 2007;357:2028-39.
Supplement
Joint Bone Spine
2nd National ODISSEE Meetings (Osteoporosis: DIagnosis and Surveillance of SEvErity)
Male osteoporosis & cortisonical osteoporosis
xxxxx
Issue produced with the institutional support of Lilly Inc.
December 2011 Vol. 79 – Supplement 2 p. S189-S226 ISSN 1297-319X
Editorial
Management of glucocorticoid-induced osteoporosis: lessons for clinical practice Christian Rouxa,*, Gérald Rajzbaumb, Gauthier Morelc, Erick Legrandd, Michel Larochee, Emmanuel Hoppéd, Florence Chopinf, Séverine Borge, Emmanuel Biverg, Bernard Cortetg, Thierry Thomasf aUniversité
Paris-Descartes, service de rhumatologie B, hôpital Cochin, 27 rue du faubourg Saint-Jacques, 75014 Paris, France de rhumatologie, groupe hospitalier Paris Saint-Joseph, 185 rue Raymond Losserand, 75674 Paris cedex 14, France cService de rhumatologie, centre hospitalier, avenue Desandrouins, BP 479, 59322 Valenciennes cedex, France dUniversité d’Angers, service de rhumatologie, CHU Angers, 4 rue Larrey, 49033 Angers cedex 01, France eService de rhumatologie, hôpital Purpan, 1 place du docteur Baylac, 31059 Toulouse, France fINSERM U1059, service de rhumatologie, CHU Bellevue, 25 boulevard Pasteur, 42055 Saint-Étienne, France gDépartement universitaire de rhumatologie, hôpital Roger Salengro, rue du Professeur Emile Laine, 59037 Lille cedex, France bService
Keywords: Glucocorticoids Fractures Osteoporosis Bone densitometry Treatment
Glucocorticoid-induced osteoporosis, the leading cause of secondary osteoporosis, results from the well-documented deleterious effects of glucocorticoids on bone [1, 2]. The prevalence of chronic glucocorticoid use is nearly 1% in the general population and up to 2.5% in individuals aged 70 to 80 years [3]. The main reasons for glucocorticoid therapy are inflammatory joint diseases and lung diseases [3, 4]. In everyday practice, glucocorticoidinduced osteoporosis is underdiagnosed and undertreated [5, 6]. Gradual improvements in diagnostic tools, together with the introduction of drugs that either diminish the need for high-dose glucocorticoid therapy or treat glucocorticoid-induced osteoporosis, can be expected to improve the management of this disorder. Following on the first national ODISSEE (Osteoporosis DIagnosis and Surveillance of SEvErity) meeting [7], the second national ODISSEE meeting held in 2010 convened a panel of national experts to exchange viewpoints on glucocorticoidinduced osteoporosis, based on a literature review conducted by the scientific committee. The experts focused on three main issues and the content of their discussions is reviewed herein.
1.
Are glucocorticoids really deleterious for bone?
Glucocorticoids have dose-dependent toxic effects on bone that are related to both direct and indirect mechanisms, and an increase in the fracture risk was seen even with low glucocorticoid dosages. Therefore, there is a recommendation to give osteoporosis medications (e.g., teriparatide or bisphosphonates) to patients who are starting or continuing long-term oral glucocorticoid therapy. Glucocorticoid therapy is effective in combatting inflammation in patients with chronic inflammatory joint disease. This effect influences the risk/benefit ratio of glucocorticoid therapy in terms of the fracture risk in patients with chronic inflammation. Although glucocorticoid therapy has been reported to increase the fracture risk in patients with rheumatoid arthritis (RA) [8], this finding should be put in balance with a number of other observations: • among patients with early polyarthritis, those whose C-reactive protein levels remain elevated during follow-up experience rapid bone loss [9];
* Corresponding author. E-mail address: [email protected] (Christian Roux). © 2011 Société française de rhumatologie. Published by Elsevier masson SAS. All rights reserved.
C. Roux et al. / Joint Bone Spine 78 (2011) S222-S226
• RA (without glucocorticoid therapy) is an independent risk factor for osteoporosis [9]; • among patients receiving aggressive treatments for recentonset RA (BeSt study), those receiving high-dose glucocorticoid therapy do not experience a faster rate of bone loss [10]; • and in patients with active RA given TNFα antagonist therapy combined with a stable methotrexate dosage and, if needed, less than 10 mg/d of prednisone, bone loss correlated initially with disease activity and disease duration but stopped after the introduction of the TNFα antagonist. The change in bone loss correlated negatively with the change in CRP. Furthermore, combination therapy with a glucocorticoid and a TNFα antagonist was associated with an increase in BMD values at the proximal femur [11]. These clinical data do not call into question the deleterious effects of glucocorticoids on bone, most notably in older individuals. However, they indicate that inflammation is also a major risk factor for bone loss, as now clearly demonstrated by pathophysiological and clinical data [12].
In practice When highly effective disease-modifying treatment is available, as is now the case in RA, oral low-dose glucocorticoid therapy to improve the control of the inflammatory process may exert beneficial effects on bone. These data are not relevant to other diseases (e.g., giant cell arteritis, respiratory diseases, and gastrointestinal diseases).
estimated at 1.33 for peripheral fractures, 1.61 for proximal femoral fractures, and 2.6 for vertebral fractures [15]. The risk increase occurred within the first 6 months of treatment.
In practice The rapid occurrence of bone loss and early fracture risk increase associated with glucocorticoid therapy warrant an early assessment of the appropriateness of osteoporosis treatment at the initiation of oral glucocorticoid therapy that is expected to be prolonged, particularly when the daily dosage is high.
2.2. Who should be treated? 2.2.1.
2.
Glucocorticoid-induced osteoporosis; when and who should we treat?
Glucocorticoid therapy induces an early phase of rapid bone loss, which is measurable after only a few months, followed by prolonged slower bone loss at a slower pace. Several recommendations about the management of glucocorticoidinduced osteoporosis have been issued, including 2003 French recommendations for oral dosages 7.5 mg/d, in which the threshold for treatment is a BMD T-score -1.5 SD [13]. More recently, the American College of Rheumatology (ACR) issued recommendations based on the FRAX tool [14]. Nevertheless, a number of specific situations continue to raise challenges, most notably the use of low daily dosages in young individuals or men.
2.1. When should treatment be started? In the General Practice Research Database in the UK, the relative risk of fractures in glucocorticoid-treated patients was
Selection based on the T-score
A dissociation has been reported between the BMD values and the fracture risk: thus the fracture risk is increased even when the decrease in BMD values versus baseline is small [16, 17]. The fracture risk increase during glucocorticoid therapy has been described as independent from BMD by some authors [18]. However, a T-score < -1.5 seems relevant for the management of the fracture risk in glucocorticoid-treated patients [19].
2.2.2. These hypotheses deserve to be evaluated in patients with RA in order to answer the following questions: Should complete glucocorticoid withdrawal be included among the goals of biologic therapy? and Should bisphosphonate therapy be continued in patients who achieve a complete remission of RA with combined disease-modifying and glucocorticoid therapy?
S223
Selection based on the glucocorticoid dosage:
• Effect on bone loss: published data on whether there is a threshold dose above which adverse bone effects occur are conflicting [20]. However, a dose of 7.5 mg/d was associated with a decrease in lumbar-spine BMD values [21, 22]. • Effect on the fracture incidence: the daily glucocorticoid dosage predicted the fracture risk, starting with the lowest dosages, i.e., <2.5 mg/d [15], in large cohorts (for which no information was given on concomitant treatments).
2.2.3.
Selection based on other risk factors
The fracture risk increase associated with glucocorticoid therapy varies little with age or sex. In contrast, the fracture incidence increases with age in glucocorticoid-treated patients. These data indicate a need for evaluating the absolute fracture risk in glucocorticoid-treated patients. There are two available risk scores, the Van Staa score [23] and the FRAX score [24]. The value of the FRAX score is limited by the binary nature of the glucocorticoid-therapy item, which takes neither the dosage nor the duration of glucocorticoid therapy into account.
In practice Although the fracture risk remains difficult to predict, the treatment decision in the individual patient should rely on a number of factor including age, menopausal status, BMD values, and the glucocorticoid dosage.
S224
3.
C. Roux et al. / Joint Bone Spine 78 (2011) S222-S226
Selecting the optimal treatment for glucocorticoid-induced osteoporosis
At glucocorticoid therapy initiation, the individual fracture risk should be evaluated. In particular, prevalent vertebral fractures should be sought, the risk profile established, and the menopausal status specified. This evaluation will guide treatment decisions about the use of medications in addition to general measures and vitamin D supplementation.
In practice Selection of a bisphosphonate relies on a discussion between the rheumatologist and patient after information about the treatment modalities and comparative safety profiles. The experts suggest giving preference to oral bisphosphonates in young patients and to intravenous bisphosphonates in patients on multiple medications and in patients with gastrointestinal contraindications to oral administration, expected poor treatment adherence, or high-dose glucocorticoid therapy.
3.1. Treatment modalities 3.1.1.
Role for vitamin D and calcium supplementation
Calcium and vitamin D deficiencies are common. In practice The experts recommend routine vitamin D supplementation. Patients whose food frequency questionnaire indicates an inadequate dietary calcium intake should receive supplemental calcium.
3.1.2.
Role for oral or parenteral bisphosphonate therapy
In France, three oral bisphosphonates (etidronate 400 mg, alendronate 5 mg, and risedronate 5 mg) are licensed for use in preventing bone loss in patients requiring glucocorticoid therapy in a dosage 7.5 mg/d prednisone-equivalent for at least 3 months. For risedronate, the license applies only to postmenopausal women. A single intravenous bisphosphonate (zoledronic acid 5 mg/year) is licensed for use in postmenopausal women and in men at high fracture risk (Table 1) [25]. Bisphosphonates improve BMD values at the lumbar spine when used to prevent or reverse GIO. The impact on femoral BMD values varies across bisphosphonates, and the fracture risk decrease is greatest in older women having low baseline BMD values at the lumbar spine.
3.1.3.
Role for teriparatide
In France, teriparatide is licensed for use in glucocorticoidinduced osteoporosis in women and men at high fracture risk receiving long-term glucocorticoid therapy. The license was granted based on a double-blind randomized trial in 428 patients with glucocorticoid-induced osteoporosis who received either alendronate 10 mg/d (n=214) or teriparatide 20 μg/d (n=214). The change in lumbar-spine BMD was significantly greater in the teriparatide group starting at the sixth treatment month. At follow-up completion, the lumbar-spine BMD increase was +7.2%±0.7% with teriparatide and +3.4%±0.7% with alendronate (P<0.001 between the two groups) [26].
In practice Teriparatide is indicated in women and men of any age who are at high fracture risk. The marketing license limits the treatment duration to 24 months, and the first 18 months are reimbursed by the French public healthcare insurance system provided the patient has at least two prevalent vertebral fractures. Consequently, imaging studies should be obtained routinely to assess the presence of prevalent vertebral fractures.
Table 1 Medications licensed for use in glucocorticoid-induced osteoporosis. NPN (brand name) Alendronate
(Fosamax®
Marketing license 5 mg)*
Treatment of osteoporosis: Prevention of bone loss in patients requiring systemic glucocorticoid therapy for longer than 3 months in a daily dosage greater than 7.5 mg of prednisone-equivalent
Etidronate (Didronel® 400 mg)**
Treatment of osteoporosis: Prevention of bone loss in patients requiring systemic glucocorticoid therapy for longer than 3 months in a daily dosage greater than 7.5 mg of prednisone-equivalent
Risedronate (Actonel® 5 mg)
Maintaining or increasing bone mass in postmenopausal women requiring long-term systemic glucocorticoid therapy (for longer than 3 months) in daily doses of at least 7.5 mg prednisone-equivalent
Zoledronic acid 5 mg/year (Aclasta® 5 mg)
Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy (>7.5 mg/d oral prednisone (or equivalent)): • in postmenopausal women • in men at high fracture risk
Teriparatide (Forsteo®)
Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy (equivalent to 5 mg or greater of prednisone for at least 3 months) in women and in men at high fracture risk
* Not available in France ** This drug is not recommended by French health authorities, as the efficacy of DIDRONEL 400 mg in preventing peripheral fractures, most notably at the femoral neck, remains unproven [25].
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3.1.4.
Treatment sequence
In practice • After 18 months of teriparatide therapy, the experts recommend bisphosphonate therapy for as long as the glucocorticoid is required. • After failure of a bisphosphonate, defined as significant bone loss or a new fracture, teriparatide therapy may be considered, according to the limits set by the marketing license and French public healthcare insurance system. • Treatment duration: the available studies didn’t determine the optimal treatment duration. In treatment trials of bisphosphonates and teriparatide, BMD values were obtained only during the first 3 years.
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Substantial contributions and financial support for research projects or as an investigator in studies sponsored by Amgen, Lilly, MSD, Novartis, Roche. Th. Thomas: Clinicial trials: as main (head) clinical or laboratory investigator, or study coordinator (Ipsen) and as coinvestigator or study contributor (Amgen, Lilly, MSD, Novartis, Servier, Warner-Chilcott); Occasional involvements: expert reports (Warner-Chilcott) and advisory services (Amgen, Lilly, Novartis, Servier, Warner-Chilcott); Conferences: attendance as contributor (Amgen, BMS, Chugai, GSK, Ipsen, Lilly, MSD, Novartis, Roche, Servier, Warner-Chilcott); Substantial contributions to the finances of a company or organisation which he is responsible (Amgen, BMS, Chugai, MSD, Novartis, Roche). This special issue was realized as part of 2nd National Meetings ODISSEE organized with the institutional support of laboratories Lilly Inc.
3.1.5.
Strategy at glucocorticoid therapy discontinuation
References In practice At discontinuation of long-term glucocorticoid therapy, the experts recommend a repeat evaluation of the fracture risk. If the risk remains high, most notably in postmenopausal women, the osteoporosis medication should be continued. In contrast, if stopping the glucocorticoid, together with the good disease control this event usually signifies, results in a low fracture risk, the osteoporosis medication can be stopped at the same time as the glucocorticoid.
Disclosures Ch. Roux received research grants and/or honoraria from Amgen, MSD, Servier, Lilly, Novartis. G. Rajzbaum: Clinical trials: as co-investigator or study contributor (Lilly, Pfizer); Occasional involvements: expert reports (Lilly, Amgen); Conferences: attendance as contributor (Lilly, Amgen, Ipsen). G. Morel: Conferences: attendance as contributor (Lilly, MSD, Roche). E. Legrand, E. Hoppé, S. Borg: no conflicts of interests. M. Laroche: Clinical trials: as main (head) clinical or laboratory investigator, or study coordinator (Lilly, Amgen, Roche, Servier, Procter & Gamble); Occasional involvements: experts reports and advisory services (Amgen, Lilly, MSD, Roche, Servier, Pierre-Fabre, Procter & Gamble, WC Pharmaceuticals, Daichi Sankio, Novartis); Conferences: attendance as contributor and as audience member (Amgen, Lilly, MSD, Roche, Servier, PierreFabre, Procter & Gamble, WC Pharmaceuticals, Daichi Sankio, Novartis); Substantial contributions to the finances of a company or organisation which he is responsible (Novartis, MSD, Amgen). F. Chopin: Clinical trials: as co-investigator or study contributor (MSD, Roche, Pfizer, Lilly). E. Biver: Conferences: attendance as contributor (Amgen, Lilly) and as audience member (Amgen, Lilly, Servier). B. Cortet: Occasional involvements: expert reports and advisory services (Amgen, Daiichi-Sankyo, Ferring, Lilly, MSD, Medtronic, Novartis, Roche, Servier, Warner & Chilcott) ;
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