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Alphagalileo.orgOsteoporos IntDOI 10.1007/s00198-012-1958-1 A framework for the development of guidelinesfor the management of glucocorticoid-induced osteoporosis S. Lekamwasam & J. D. Adachi & D. Agnusdei &J. Bilezikian & S. Boonen & F. Borgström & C. Cooper &A. Diez Perez & R. Eastell & L. C. Hofbauer & J. A. Kanis &B. L. Langdahl & O. Lesnyak & R. Lorenc &E. McCloskey & O. D. Messina & N. Napoli &B. Obermayer-Pietsch & S. H. Ralston & P. N. Sambrook &S. Silverman & M. Sosa & J. Stepan & G. Suppan &D. A. Wahl & J. E. Compston &Joint IOF-ECTS GIO Guidelines Working Group Received: 23 December 2011 / Accepted: 13 February 2012 # International Osteoporosis Foundation and National Osteoporosis Foundation 2012 Osteoporosis Foundation and the European Calcified Tissue Summary This paper provides a framework for the devel- Society, which set up a joint Guideline Working Group at the opment of national guidelines for the management of glu- end of 2010.
cocorticoid-induced osteoporosis in men and women aged Methods and results The epidemiology of GIO is reviewed.
18 years and over in whom oral glucocorticoid therapy is Assessment of risk used a fracture probability-based ap- considered for 3 months or longer.
proach, and intervention thresholds were based on 10-year Introduction The need for updated guidelines for Europe and probabilities using FRAX. The efficacy of intervention was other parts of the world was recognised by the International assessed by a systematic review.
These guidelines have been endorsed by the Committee of ScientificAdvisors of the IOF and the ECTS Board and Professional PracticeCommittee. An appendix to these guidelines can be found in Archivesof Osteoporosis (DOI Department of Medicine, Faculty of Medicine, Quantify Research and LIME/MMC, Karolinska Institutet, Centre for Metabolic Bone Diseases, Stockholm, Sweden Division of Rheumatology, Department of Medicine, MRC Lifecourse Epidemiology Unit, University of Southampton, McMaster University, Southampton General Hospital, Southampton and NIHR Hamilton, ON, Canada Musculoskeletal Biomedical Research Unit,Institute of Musculoskeletal Sciences, University of Oxford, Eli Lilly and Co.,Florence, Italy Hospital del Mar-IMIM-Universitat Autónoma, College of Physicians and Surgeons, Columbia University, R. Eastell E. McCloskey Division of Gerontology and Geriatrics and Center for Academic Unit of Bone Metabolism, University of Sheffield and Musculoskeletal Research, Department of Experimental Medicine, NIHR Musculoskeletal Biomedical Research Unit, Sheffield Leuven University, Teaching Hospitals NHS Trust, Conclusions Guidance for glucocorticoid-induced osteopo- early after therapy is initiated, emphasising the importance of rosis is updated in the light of new treatments and methods primary prevention of fracture in high-risk individuals ].
of assessment. National guidelines derived from this re- Most currently available guidelines for the management of source need to be tailored within the national healthcare GIO were developed prior to the release of FRAX® and other framework of each country.
risk assessment tools and the approval of newer pharmacolog-ical interventions for its management In 2010, the Amer- Keywords Bone mineral density . Bone-protective therapy .
ican College of Rheumatology (ACR) revised its 2001 Fracture . FRAX . Glucocorticoids recommendations to incorporate advances in risk assessmentand to include all currently approved treatments The needfor updated guidelines for Europe and other parts of the world was recognised by the International Osteoporosis Foundation(IOF) and the European Calcified Tissue Society, which set up a Osteoporosis is a common complication of glucocorticoid joint Guideline Working Group at the end of 2010. The aim of therapy and is associated with substantial morbidity. Although this group was to provide a framework for the development of awareness of the condition has grown in recent years, it guidelines from which country-specific recommendations could remains under-diagnosed and under-treated. Glucocorticoid- be derived. The framework covers the management of GIO in induced osteoporosis (GIO) has distinct characteristics; in men and women aged 18 years or over, in whom continuous particular, rapid bone loss and increased fracture risk occur oral glucocorticoid therapy at any dose is considered for Division of Endocrinology, Diabetes, and Bone Diseases, University of Sydney-Royal North Shore Hospital, Department of Medicine III, St Leonards, Sydney, Australia Dresden Technical University Medical Center,Dresden, Germany Cedars-Sinai/University of California, Centre for Metabolic Bone Diseases (WHO Collaborating Centre), Los Angeles, CA, USA University of Sheffield Medical School,Sheffield, UK Investigation Group on Osteoporosis, Hospital University Insular, Department of Endocrinology, Aarhus University Hospital, Bone Metabolic Unit, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Canary Islands, Spain O. LesnyakRussian Association on Osteoporosis, Yekaterinburg, Russia Institute of Rheumatology,Prague, Czech Republic R. LorencDepartment of Biochemistry and Experimental Medicine,The Children's Memorial Health Institute, Faculty of Medicine 1,Charles University, Prague, Czech Republic Department of Rheumatology, C. Argerich Hospital,Buenos Aires, Argentina Action for Healthy Bones, Division of Endocrinology, Campus Bio-Medico University, B. Obermayer-Pietsch J. E. Compston (*) Division of Endocrinology and Metabolism, International Osteoporosis Foundation, Department of Internal Medicine, Medical University of Graz, Nyon, Switzerland S. H. RalstonRheumatic Diseases Unit, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Department of Medicine, Western General Hospital, University of Edinburgh, Cambridge University Hospitals NHS Foundation Trust, 3 months or longer. All interventions approved for GIO world- 42,500 men and women from seven prospective cohorts wide are included, and the content will be updated at intervals.
followed for 176,000 patient years, previous or current The recommendations in this document are provided to glucocorticoid use was associated with a significantly aid management decisions for physicians in primary and increased risk of any fracture, osteoporotic fracture or hip secondary care but do not replace the need for physician fracture, the highest gradients of risk being seen for hip judgement in the care of individuals in clinical practice. It is fracture. Increased fracture risk was seen at all ages from recognised that guidance will vary between countries be- 50 years upwards and was similar in men and women cause of differences in resources, availability and cost of Following withdrawal of glucocorticoid therapy, fracture risk treatments and health care policies.
decreases, consistent with the spontaneous improvement inBMD reported after successful treatment of Cushing's syn-drome. A residual risk remains, possibly related to the under- Epidemiology of GIO lying disorder for which glucocorticoids were prescribed.
Most of the available epidemiological data relate to oral Oral glucocorticoids are prescribed for a wide variety of glucocorticoid therapy given continuously for 3–6 months medical disorders, most commonly musculoskeletal disor- or longer. There is some evidence that high doses of inhaled ders and obstructive pulmonary disease In a multina- glucocorticoids may be associated with reduced BMD and a tional population-based prospective observational study of small increase in fracture risk [Increased fracture risk 60,393 postmenopausal women who had visited their pri- has also been reported with intermittent oral glucocorticoid mary care practice within the last 2 years, the Global Lon- gitudinal Study of Osteoporosis in Women, up to 4.6% werecurrently taking oral glucocorticoids, depending on theircountry of origin [ Glucocorticoid receptors are expressed on various extraske- Epidemiology of glucocorticoid-induced osteoporosis• letal and skeletal cells. The pathogenesis of GIO is thought Up to 4.6% of postmenopausal women are reported as currently taking oral glucocorticoids.
to result from direct effects of exogenous glucocorticoids on • Fracture risk increases during the first 3–6 months of glucocorticoid bone cells and indirect effects mediated by altered calcium therapy and decreases following their withdrawal.
handling by the kidneys and the gut, reduced production of • An increase in fracture risk occurs with low doses and rises further gonadal hormones and detrimental effects on the neuromus- with increasing daily dose.
cular system, which may increase the risk of falls [ • The greatest increase in risk is seen for vertebral fracture; in patients Through activation of their high-affinity receptors, gluco- taking ≥7.5 mg/day prednisolone or its equivalent, a relative risk of corticoids modify the biology of all three major bone cells, 5.18 (95% CI 4.25–6.31) has been reported.
osteoblasts, osteoclasts and osteocytes. While physiologicalconcentrations of glucocorticoids are indispensible for differ- Data from the General Practice Research Database entiation of mesenchymal stromal cells into osteoblasts in (GPRD) in the UK have demonstrated that fracture risk is vitro, exogenous glucocorticoids inhibit osteoblasts at several increased even with relatively low daily doses (2.5–7.5 mg) levels Thus, pluripotent mesenchymal stromal cells may of prednisolone or its equivalent and rises further with be shifted towards the adipocytic pathway at the cost of the increasing daily dose [Although the cumulative dose osteoblastic pathway when exposed to glucocorticoids of glucocorticoids correlates strongly with bone loss The most consistent skeletal effects of glucocorticoids are to assessed by BMD measurements, the association with frac- inhibit osteoblast function and to promote osteoblast apopto- ture risk is weaker than that for daily dose ]. Increased sis. Mechanisms involved are decreased osteoblastic produc- fracture risk is seen within the first 3–6 months after starting tion of bone anabolic factors insulin-like growth factor-1 and glucocorticoids, the greatest risk being seen for vertebral transforming growth factor beta, interference with the Wnt fracture ]. In patients taking ≥7.5 mg/day prednisolone or signalling pathway with upregulation of Wnt inhibitors such its equivalent, the relative rate of vertebral fracture was 5.18 as Dickkopf-1 and sclerostin and alterations of the bone (95% CI 4.25–6.31), compared to 2.27 (2.16–3.10) for non- matrix composition by altered production of type 1 collagen vertebral fracture. The high risk of vertebral fractures in and overproduction of inhibitors of matrix mineralization glucocorticoid-treated patients is also emphasised by the , ]. In addition, apoptosis of osteoblasts and results of a recent study in which 24% of glucocorticoid- osteocytes is enhanced by glucocorticoids leading to a shorter treated patients previously treated with alendronate or alfa- life span of bone-forming and mechanosensing cells calcidol developed new vertebral fractures during the 2.7- Some of these pro-apoptotic effects of glucocorticoids may year follow-up period [In a meta-analysis of data from be prevented by PTH and by bisphosphonates ].
Effects on osteoclasts are somewhat controversial and averaged (Table 1, Appendix; Archives of Osteoporosis may involve both osteoblast-mediated and direct actions . Glucocorticoids upregulate the ratio of receptoractivator of NF-κB ligand (RANKL) to osteoprotegerin by Hand search of abstracts osteoblasts, most likely as a direct consequence of sup-pressed osteoblast differentiation, which translates into Meeting abstracts from 1 April 2009 to 31 Dec 2010 were increased osteoclastogenesis , ]. Glucocorticoids also hand searched. Abstracts of the annual meetings of the interfere with the ruffled border of the osteoclast; in addition, American College of Rheumatology, International Osteopo- mice with a targeted deletion of the osteoclastic glucocorti- rosis Foundation-European Congress on Clinical and Eco- coid receptor were protected against suppression of bone nomic Aspects of Osteoporosis, the European League formation following glucocorticoid exposure, indicating that Against Rheumatism, American Society for Bone and Min- glucocorticoids signal through the osteoclast to modulate eral Research, and European Calcified Tissue Society were osteoblast function ]. It should be noted that these searched for clinical trials that met the criteria described concepts of pathogenesis are predominantly based on above. The search identified eight abstracts.
observations made in preclinical models and have notbeen validated in humans.
Grading of recommendations The grading of recommendations was derived as follows: Methods and search strategy Level of grade of evidence/type of evidence recommendation Systematic search Ia. Meta-analysis of RCTs/A The systematic search published in the ACR guidelines was Ib. At least one RCT/A updated to include the period of 1 April 2009 to 31 December IIa. At least one well-designed, controlled study but with- 2010. The systematic search for clinical trials in patients taking out randomization/B oral glucocorticoids was conducted in MEDLINE through IIb. At least one well-designed, quasi-experimental study/B PubMed using the search terms described below. Only the ap- III. At least one well-designed, non-experimental descrip- proved therapeutic agents agreed by the panel, etidronate, alen- tive study (e.g. comparative studies, correlation studies, dronate, risedronate, zoledronic acid, vitamin D alfacalcidol, calcitriol, calcium, teriparatide and PTH, were in- IV. Expert committee reports, opinions and/or experience cluded in the search. In MEDLINE, both Free Text and MeSH of respected authorities/C search options were used. A similar search was performed in theCochrane Trial Registry (CENTRAL) to ensure the complete- Assessment of fracture risk ness of the search. Furthermore, the Clinical Queries option (withthe Broader and Sensitive filter) of PubMed was searched to FRAX® is a computer-based algorithm capture systematic reviews and randomized controlled trials that calculates the 10-year probability of a (RCTs). The PubMed search was limited to RCTs, controlled major fracture (hip, clinical spine, humerus or wrist fracture) clinical trials, systematic surveys and meta-analysis, age and the 10-year probability of hip fracture – (18 years or over) and publications in the English language. Only Fracture probability differs markedly in different regions studies with information on BMD and/or fracture and with a of the world [so that FRAX is calibrated to those minimum follow-up period of 6 months were included. Studies countries where the epidemiology of fracture and death is involving transplant recipients were excluded. Ninety-four known (currently 40 countries). It is the recommended articles were identified by the MEDLINE search, of which seven method of risk assessment in an increasing number of guide- met the criteria for inclusion. Eleven further articles were iden- tified by the CENTRAL search of which one met the inclusioncriteria (see Table 1, Appendix; Archives of Osteoporosis DOI Assessment of risk A general approach to risk assessment is shown in Fig. Quality rating of studies ]. The management process begins with the assessmentof fracture probability and the categorization of fracture risk The quality of published studies was assessed using the on the basis of age, sex, body mass index (BMI) and clinical Jadad score ]. Studies were assessed independently by risk factors. On this information alone, some patients at high three members of the working group, and the scores were risk may be offered treatment without recourse to BMD testing. There will be other instances where the probability For higher doses of prednisolone, greater upward adjust- is so low that a decision not to treat can be made without ment of fracture probability may be required. Data from the BMD. The size of the intermediate category in Fig. will GPRD indicate that in patients with a daily dose of 20 mg/day vary in different countries. In countries that provide reim- of prednisolone or its equivalent, the excess risk of non- bursement for DXA, this will be a large category, whereas in vertebral fracture was increased approximately threefold com- a large number of other countries with limited or no access pared to those taking ≤5 mg/day or its equivalent  and that to densitometry, the size of the intermediate group will this risk increases further with even higher doses.
necessarily be small. In other countries (e.g. the UK), where The same principles apply to other risk factors used in provision for BMD testing is sub-optimal [the interme- FRAX in that probability assessments need to be tempered diate category will lie between the two extremes. The ratio- by ancillary information of clinical relevance [Exam- nale for the use of FRAX in the absence of access to BMD ples include a high falls risk, multiple prior fractures, im- or limited access has been recently reviewed ].
mobility and severe rheumatoid arthritis. Since spine BMDcannot be entered into FRAX, fracture risk might be under- FRAX adjustment for dose of oral glucocorticoids estimated in individuals in whom BMD is substantiallylower in the spine than in the hip. A simple procedure has One of the limitations of FRAX is that use of oral gluco- been described to incorporate the offset between spine and corticoids is entered as a dichotomous risk factor (yes/no) hip BMD in such cases that enhances prediction of both and does not take into account the dose of glucocorticoids.
vertebral and major osteoporotic fracture risk [In addi- Neither does it accommodate the duration of use, except that tion, clinical, but not morphometric, vertebral fractures are exposures of less than 3 months should not be entered ].
included in the major osteoporotic probabilities generated For longer-term use, FRAX assumes an average risk, pro- by FRAX, and the risk of all vertebral fractures may be viding hazard ratios for an average dose and duration of exposure to glucocorticoids . As expected, higher-than-average daily doses of oral glucocorticoids (2.5–7.5 mgprednisolone or its equivalent) are associated with higherrisks of fracture while lower-than-average doses are associ- Intervention thresholds ated with lower risks [, ].
Recommendations for intervention thresholds in GIO arecontentious and have a weaker evidence base than in Use of FRAX in glucocorticoid-induced osteoporosis postmenopausal osteoporosis. The revised ACR guide- • Oral glucocorticoid use is entered into FRAX as a dichotomous risk lines recommend treatment in postmenopausal women factor and does not take into account the daily dose or duration ofuse.
and men aged 50 years or older starting on oral gluco- • FRAX assumes an average dose of prednisolone (2.5–7.5 mg/day or corticoids with a FRAX-derived 10-year probability of its equivalent) and may underestimate fracture risk in patients taking major osteoporotic fracture of over 10 % and in those higher doses and overestimate risk in those taking lower doses.
with a probability of less than 10 % if the daily dose of • Using UK data, the average adjustments over all ages in prednisolone or its equivalent is ≥7.5 mg/day. The postmenopausal women and men aged ≥50 years are 0.65 for daily threshold of >10 % in patients taking ≥7.5 mg/day is doses <2.5 mg/day prednisolone or its equivalent and 1.20 for dailydoses ≥7.5 mg/day prednisolone or its equivalent for hip fracture,and 0.8 and 1.15, respectively, for major osteoporotic fracture.
• For high doses of glucocorticoids, greater upward adjustment of fracture probability may be required.
Under certain assumptions, relatively simple arithmetic procedures have been formulated which can be applied toconventional FRAX estimates of probabilities of hip fracture and a major osteoporotic fracture to adjust the probability assessment with knowledge of the dose of glucocorticoids(Table ) ]. For example, a woman aged 60 years from the UK taking glucocorticoids for rheumatoid arthritis (noother risk factors and BMI of 24 kg/m2) has a 10-year probability for a major fracture of 13%. If she is on a higher-than-average dose of prednisolone (>7.5 mg daily orits equivalent), then the revised probability should be 15% Fig. 1 Management algorithm for the assessment of individuals at risk of fracture CRFs clinical risk factors considerably lower than that used in postmenopausal osteo- Table 1 Average adjustment of 10-year probabilities of a hip fractureor a major osteoporotic fracture in postmenopausal women and older porosis (20%) .
men according to dose of glucocorticoids National guidelines for the management of GIO have been published in some other countries including Canada, Prednisolone equivalent Average adjustment over all Belgium, France, Japan, Italy, Spain and the UK [, but in many countries, national guidelines are not available. Approaches used to set intervention thresholds depend critically on local factors such as reimbursement policies, health economic assessment, willingness to pay for health care in osteoporosis and access to DXA [, Major osteoporotic fracture , ]. For this reason, it is not possible or desirable to recommend a unified intervention strategy.
In non-glucocorticoid-treated postmenopausal women with osteoporosis, most guidelines recommend that womenwith a prior fragility fracture may be considered for inter- Adapted from ], with kind permission from Springer Science+ vention without the necessity for a BMD test (other than to Business Media B.V.
monitor treatment) , ]. In the UK, theintervention threshold in women without a prior fracture is Clinical scenarios for glucocorticoid-induced osteoporosis set at the age-specific fracture probability equivalent to women with a prior fragility fracture ] and therefore riseswith age. Using this criterion, intervention thresholds will Table shows several clinical scenarios applied to the vary from country to country because the population risks of assessment strategy of NOGG (limited access to BMD). At fracture and death vary , ] (Table ).
an intervention threshold of around 20%, the majority of An example of a strategy that has been adopted in the UK patients aged ≥70 years and/or with a previous fracture is given below. It is similar to strategies commonly applied would be considered eligible for treatment. In addition, in Europe in the context of postmenopausal osteoporosis, those aged 50–70 years who are on high doses of glucocor- but takes into account the marked variations in access to ticoids could be considered eligible for treatment, depending DXA in different European countries ]. The approach, on the dose and other clinical risk factors. In the remaining originally applied by the National Osteoporosis Guideline situations, a T-score of approximately −1.5 or lower is Group (NOGG) in the UK, has been validated –].
required. Similar recommendations are made for men, sincethe effectiveness and cost-effectiveness of intervention in & If no access to DXA is available, assessment of fracture men with osteoporosis are broadly similar to those of post- probability is determined using FRAX and treatment menopausal osteoporosis for an equivalent risk [, considered for those in whom fracture probability lies These recommendations make the plausible but untested above the intervention threshold.
assumption that the independent contribution to fracture risk & If access to DXA is available, the use of FRAX demands of most diseases for which glucocorticoid therapy is pre- not only consideration of the fracture probability at scribed is similar to that of rheumatoid arthritis.
which to intervene (intervention threshold) but also thefracture probability for BMD testing (assessment thresh- Indications for bone-protective therapy in postmenopausal women and olds) . Assessment thresholds for the UK are men ≥50 years on glucocorticoid therapy shown in Fig.
• Aged ≥70 years & If access to DXA is limited, those with fracture proba- • Previous fragility fracture or incident fragility fracture during bilities above the lower assessment threshold but below glucocorticoid therapy the upper assessment threshold can be considered for • High doses of glucocorticoids, depending on daily dose and presence BMD testing and their fracture probability reassessed.
or absence of other clinical risk factors Treatment can then be considered in those with a frac- • BMD T-score ≤−1.5 ture probability above the intervention threshold.
& If unlimited access to DXA is available, all those with fracture probabilities above the lower assessment thresh-old can be considered for BMD testing and their fracture probability reassessed. Treatment can then be consideredin those with a fracture probability above the interven- A full clinical history should be taken, including details of tion threshold.
co-morbidity, glucocorticoid use (previous or ongoing,
Table 2 Examples of intervention thresholds (equivalent to the age- Table 3 Clinical scenarios for women in the UK (BMI 024 kg/m2) specific fracture probability in women with prior fragility fracture) as showing the 10-year probability of a major fracture by age for a high set by FRAX-based 10-year probability (in percent) of a major osteo- dose of glucocorticoids (GC) (>7.5 mg/day) using the adjustment porotic fracture in postmenopausal women with a previous fracture (no factor , an average dose of glucocorticoids (2.5–7.5 mg/day) in a glucocorticoid treatment or other clinical risk factors, a body mass woman with rheumatoid arthritis (RA), and an average dose of gluco- index of 24 kg/m2 and without BMD) [ corticoids with a prior fracture (Fx) dosage, duration and route of administration), fracture his- The numbers in parentheses represent the approximate T-scores atwhich the probability would lie at or above the NOGG intervention tory (type and trauma), alcohol intake, smoking, height loss, threshold (FRAX version 3.4 for the UK) family history of osteoporosis and hip fracture. The history a Recommended BMD test should include an assessment of dietary calcium intake, b Recommended treatment obtained either informally or using a food frequency ques-tionnaire. Height and weight should be measured. Routinebiochemical testing should be performed to exclude causes considered in patients with back pain, documented loss of of secondary osteoporosis other than glucocorticoid use height or kyphosis, or low BMD.
including assessment of vitamin D status and renal function(Table ). Measurement of BMD by DXA at the spine andhip is generally recommended. Lateral imaging DXA with Management of glucocorticoid-induced osteoporosis vertebral fracture assessment (VFA) is of value in detecting existing vertebral fractures ], but if this is not available,lateral X-rays of the thoracic and lumbar spine should be General measures in the management of GIO Certain general measures can be advocated in individualstaking glucocorticoids, although the evidence base for theireffects on fracture risk is weak (Table ). The dose ofglucocorticoids should be regularly reviewed and kept toa minimum. Alternative routes of administration (e.g.
topical, inhaled) or formulations (e.g. budesonide) may beconsidered, and in some situations, use of alternative immu-nosuppressive agents may enable reduction in the dose ofglucocorticoids. Adequate levels of dietary calcium intake,good nutrition and maintenance of a normal body weightshould be encouraged. Tobacco use and alcohol abuse shouldbe avoided, and appropriate levels of physical exercise shouldbe encouraged. Falls risk assessment and, where appropriate,advice to reduce the risk of falls should be performed in thoseat increased risk of falling.
Fig. 2 Assessment guidelines of the UK National Osteoporosis Guide-line Group based on the 10-year probability of a major fracture (in percent). The dotted line denotes the intervention threshold. Whereassessment is made in the absence of BMD, a BMD test is recommen- Although a number of interventions have been evaluated in ded for individuals where the probability assessment lies in the mid-region. Adapted from ] the management of GIO, the strength of evidence for their Table 4 Investigations to ex-clude causes of secondary Full blood count and ESR Exclude anaemia; high ESR may suggest monoclonal Creatinine, urea, eGFR Exclude chronic kidney disease Calcium, phosphate, alkaline phosphatase, Exclude primary hyperparathyroidism, malignancy, osteomalacia, Paget's disease Liver function tests Exclude chronic liver disease, alcohol abuse Oestrogen, testosterone, LH, FSH Exclude hypogonadisma IgA anti-tissue transglutaminase antibody or IgA Exclude coeliac disease endomysial antibody Immunoglobulins, Bence Jones Protein, serum Exclude monoclonal gammopathy free light chains Exclude vitamin D deficiency aNot required in women who are Exclude hyperthyroidism known to be postmenopausal efficacy is weaker than that for postmenopausal osteoporo- In the case of alfacalcidol , and calcitriol sis, since fracture reduction has not been a primary end point similar evidence exists for spine BMD, but data of any study. This reflects the acceptance by regulatory for effects on hip BMD are inconsistent. Evidence for ver- authorities of bridging studies, using BMD, for agents pro- tebral fracture reduction, albeit not as a primary end point, posed for GIO that have been shown to reduce fractures in was reported in placebo-controlled or comparator studies for postmenopausal osteoporosis Fracture data in GIO alendronate [etidronate [risedronate ] and ter- studies are therefore only available as secondary end points iparatide , ]. The lower grading for alendronate reflects or as safety data. Studies in GIO are limited further by their the omission, in the extension study, of patients who had short duration and heterogeneity of trial populations with fractured during the first year of the study. No data are respect to age, sex, underlying disease, co-morbidities, con- available for non-vertebral fractures or hip fractures.
current medications and the variable timing of intervention Since no treatment studies were designed to demonstrate in relation to initiation of glucocorticoid therapy. In addi- fracture reduction and, with the exception of four studies tion, the number of men and premenopausal women in these , ], there are no head-to-head comparisons of studies has generally been low, so the evidence for treatment interventions, inferences about the relative efficacy of dif- of these other groups is weak.
ferent treatments cannot be made. In the comparator studies,superiority of BMD change was shown for zoledronic acidover risedronate [Teriparatide was significantly more Pharmacological interventions in glucocorticoid-induced osteoporosis• effective than alendronate in increasing BMD and in reduc- Bone-protective treatment should be started at the onset of gluco- corticoid therapy in patients at increased risk of fracture.
ing vertebral fracture, although the latter was not a primary • Alendronate, etidronate, risedronate, zoledronic acid and teriparatide end point , ]. The weaker evidence for alfacalcidol and are the front-line therapeutic options for the majority of patients.
calcitriol with respect to changes in hip BMD helps to • If glucocorticoid therapy is stopped, withdrawal of bone-protective establish bisphosphonates and teriparatide as the front-line therapy may be considered, but if glucocorticoids are continued long options for the majority of patients. In clinical practice, the term, bone protection should be maintained.
• Adequate calcium intake should be achieved through dietary intake if possible, with the use of supplements if necessary.
Table 5 General measures in the management of GIO • An adequate vitamin D status should be maintained, using supplements if required.
Table summarizes the grading of recommendation for Reduce dose of glucocorticoid when possible pharmacological interventions approved for management of Consider glucocorticoid-sparing therapy GIO. For the bisphosphonates, alendronate –], etidronate Consider alternative route of glucocorticoid ], risedronate –] and zoledronic acid and for the osteoanabolic, teriparatide, there is good evidence from Advise good nutrition especially with calcium and placebo-controlled or comparator studies of beneficial effects Regular weight-bearing exercise on spine and hip BMD , The wording of the indication Avoid tobacco use and alcohol abuse for GIO varies between countries, but in EU countries, no Assess falls risk and give advice if appropriate distinction is made between prevention and treatment.
Fig. 3 Postmenopausal womenand men aged ≥50 years choice of treatment in individual patients will be mainly withdrawal of bone protection may be considered with influenced by cost and tolerability.
reassessment of fracture risk, preferably including a mea- Because rapid bone loss and increased fracture risk occur surement of BMD. In those who continue to take glucocor- soon after the initiation of glucocorticoid treatment, bone- ticoids long term, treatment should be continued. In patients protective therapy should be started at the onset of gluco- treated with teriparatide, anti-resorptive therapy should be corticoid therapy in individuals at increased risk of fracture.
considered following the permitted treatment duration of If glucocorticoid therapy is subsequently stopped, 24 months .
Fig. 4 Premenopausal womenand men aged ≤50 years Table 6 Grading of evidence for pharmacological interventions used and active vitamin D metabolites were included and com- in the management of GIO pared with calcium alone or placebo [, ]. Both anal- yses showed a beneficial effect of combination therapy on BMD. In contrast, other outcomes including fracture inci-dence were not significantly affected. There is no evidence that active vitamin D metabolites are more effective than native vitamin D (cholecalciferol, vitamin D3) in preventing bone loss or fractures in glucocorticoid-treated patients ]. However, the risk of developing hypercalcaemia and hypercalciuria is higher with active metabolites.
Based on the available evidence, current UK guidelines recommend an adequate calcium and vitamin D intake to allindividuals on glucocorticoids for three or more months nae not adequately evaluateda Similarly, the updated recommendations from the American College of Rheumatology recommend a total daily calcium Data inconsistent intake of 1,200 to 1,500 mg with 800 to 1,000 IU (20– Not a primary end point 25 μg) vitamin D for all patients starting glucocorticoidtherapy Although some recent studies have suggested Calcium and vitamin D an association between use of calcium and vitamin D sup-plementation and risk of cardiovascular disease, this Because glucocorticoid therapy is associated with reduced remains controversial , ]. Where possible, dietary intestinal and renal calcium absorption and increased uri- means should be used to achieve an adequate intake of nary calcium excretion, increasing calcium intake seems a calcium and the use of supplements reserved for individuals logical approach . However, in most studies in which with low intakes.
calcium alone served as the control therapy, bone loss wasnot prevented by calcium supplementation. For instance,despite a daily dose of 500 mg [800 mg  or even Cost-effectiveness of the treatment of GIO 1,000 mg ] of calcium, lumbar spine BMD continued todecline in patients on at least 7.5 mg/day of prednisone (by Although the cost-effectiveness of treatments for osteoporo- 2.8, 4.6 and 4.3 % over 12 months, respectively). These sis has been assessed in a number of studies [few findings suggest that calcium alone may not be sufficient have specifically addressed GIO , –]. However, if to prevent glucocorticoid-induced bone loss the assumption is made that drugs provide similar efficacy Calcium supplementation should be combined with vita- and safety in GIO as observed for postmenopausal osteopo- min D as patients on glucocorticoids commonly have vita- rosis , cost-effectiveness estimates for PMO can be min D insufficiency ]. Combined calcium and vitamin transferred to GIO at equivalent fracture risk.
D supplementation—either native vitamin D [or acti- A pan-European study from 2004 estimated the cost- vated vitamin D metabolites ]—was more effective in effectiveness of branded alendronate in nine countries in preserving BMD than either calcium alone or no therapy. In a non-glucocorticoid-treated postmenopausal women [ 2-year randomized trial in patients with rheumatoid arthritis In this study, alendronate was shown to be cost saving receiving a mean daily dose of 5.6 mg prednisone, patients on compared to no treatment in women with osteoporosis (with 1,000 mg calcium and 500 IU (12.5 μg) vitamin D3 daily had and without previous vertebral fracture) from the Nordic significant gains in BMD (0.7 and 0.9% per year at the spine countries (Norway, Sweden and Denmark). The cost- and hip, respectively), while those on placebo lost BMD (at a effectiveness of alendronate compared to no treatment was yearly rate of 2.0 and 0.9%, respectively) ]. Similarly, in a also within acceptable ranges in Belgium, France, Germany, 1-year randomized trial, patients receiving high doses of glu- Italy, Spain and the UK. However, with the decreased price cocorticoids (prednisone ≥30 mg per day) gained lumbar spine of generic alendronate, analyses based on a branded drug BMD 0.39% over 1 year when randomized to calcium 405 mg price have become obsolete and would require an update.
plus alfacalcidol 1 μg daily. In contrast, patients randomized to In a study from the UK by Kanis et al. [generic calcium alone lost BMD at a rate of 5.7% ].
alendronate was shown to be cost effective in the prevention Two meta-analyses have confirmed the beneficial effect and treatment of fractures in postmenopausal women with a of combined calcium and vitamin D in the prevention of 10-year fracture probability for a major fracture that glucocorticoid-induced osteoporosis. In these analyses, both exceeded 7.5%. Thus, the treatment scenarios envisaged trials with calcium and native vitamin D and with calcium by NOGG can be considered as cost effective (Table Other drugs that are approved for GIO (risedronate, teripara- glucocorticoid-treated patients who are at increased risk of tide and zoledronic acid) are associated with higher cost- effectiveness ratios compared to no treatment mainly due totheir higher price. A recent study by Borgström et al. , Osteonecrosis of the jaw again conducted in a UK setting, showed that risedronatewas cost effective above a 10-year probability of 13% for a An increased risk of osteonecrosis of the jaw (ONJ) has major osteoporotic fracture. However, the cost-effectiveness been reported in patients treated with bisphosphonates, par- of different interventions will vary between countries due to ticularly in those exposed to high doses of bisphosphonates differences in drug costs, fracture risk, costs of treating for treatment of skeletal malignancy. In patients treated with fractures, utility estimates and willingness to pay.
the lower doses used for osteoporosis, however, the inci-dence of ONJ is very low (between 1/10,000 and 1/100,000person exposure years) Although glucocorticoid Safety of treatments in GIO therapy has been reported in some cases of bisphosphonate-associated ONJ, there is no evidence that ONJ is more Treatment studies in GIO have generally been smaller and common in bisphosphonate-treated patients taking gluco- of shorter duration than those in postmenopausal osteopo- corticoids than in those treated with bisphosphonates alone rosis so that information on adverse effects, particularly those occurring with long-term treatment, is relatively In patients receiving treatment for GIO who are at in- sparse. Adverse events might be expected to occur more creased risk of fracture, therefore, the benefit/risk balance of frequently in glucocorticoid-treated individuals because of bisphosphonate therapy is strongly positive. However, co-morbidities and co-medications. However, there is no because of the well-established role of dental disease positive evidence to indicate that the safety profile of and trauma in the pathogenesis of ONJ, where possible, bisphosphonates and other drugs used in GIO differs signif- invasive dental procedures should be avoided in patients icantly from that observed in women treated for postmeno- taking bisphosphonates, and pre-existing severe dental disease should be treated prior to initiation of bisphosph-onate therapy. In addition, patients should be instructedto maintain good oral health.
Atypical femoral fractures Recently, concerns have arisen about a possible association Bisphosphonates and pregnancy between bisphosphonate use and atypical subtrochantericand femoral shaft fractures (AFFs) [, These frac- The use of bisphosphonates in women of childbearing age tures are rare, comprising approximately 1% of all hip and raises potential concerns about fetal safety because of the femoral fractures ], but carry a high morbidity. Al- long half-life of bisphosphonates in bone and their ability to though epidemiological studies have reported conflicting cross the maternal placenta. In animal models, high doses of results on whether bisphosphonate therapy is associated bisphosphonates cause fetal underdevelopment and skeletal with increased risk of AFFs, several recent studies indicate retardation [However, data in humans are available an association between duration of bisphosphonate use and only from sporadic clinical cases, and no systematic studies the incidence of AFFs [Glucocorticoids have have been conducted. A review of the scientific literature been proposed as a risk factor for the development of AFFs evaluated a total of 58 women treated with bisphosphonates in a number of studies –], although in a recent just before or during pregnancy and found no evidence of case control study in which atypical fractures were con- abnormalities in the offspring . Two cohort studies firmed radiologically, the use of glucocorticoids was not analysing pregnancy outcomes in women treated with associated with increased risk of AFFs in patients who were bisphosphonates up to the third month of pregnancy taking bisphosphonates .
reported no obvious excess of adverse fetal outcomes, al- A causal association between bisphosphonate use and though one case of Apert's syndrome (an autosomal domi- AFFs and the possible role of glucocorticoids in the patho- nant condition associated with a fibroblast growth factor 2 genesis of these fractures remain to be firmly established.
mutation causing acrocephalosyndactyly) occurred in a Nevertheless, imaging should be considered in patients tak- woman exposed to bisphosphonates [, ing bisphosphonates who develop unexplained thigh or Although overall these data are reassuring, bisphospho- groin pain. In view of the rare occurrence of AFFs and the nates should be avoided in premenopausal women, most of proven efficacy of bisphosphonates, the overall benefit/risk whom have a low absolute risk of fracture, unless there are balance of bisphosphonate therapy is strongly positive in strong indications for treatment (see ).
In postmenopausal osteoporosis, there is growing evi- dence that biochemical markers have potential value in The goal of bone-protective therapy in glucocorticoid- monitoring the response to treatment [their use in treated individuals is to reduce the risk of fractures. Minimal monitoring treatment in glucocorticoid-treated patients is follow-up includes verification that the patient is taking the less well established but is an important area for future medication, that the dosing procedure for the drug is appro- research. Absence of an increase in serum PINP after priate and that the patient is taking sufficient calcium and 3 months of teriparatide may identify patients in whom vitamin D. During follow-up, a careful assessment of new adherence is sub-optimal . It should be noted that the fractures should be included; rib and vertebral fractures are underlying disease may itself affect bone turnover markers particularly common in GIO. Annual height measurements (BTMs), and the relationship between changes in BTMs and should be included in the monitoring visit, and spine radio- fracture risk has not been evaluated in GIO.
graphs or vertebral fracture assessment (VFA) by DXAshould be obtained if there has been significant height loss(more than 2 cm) or if there are other symptoms or signs that Management of GIO in younger men raise suspicion of fracture (note that vertebral fractures are and premenopausal women often asymptomatic in GIO) (Table However, the inci-dence of fragility fractures on treatment is low, and absence Younger men (≤50 years) of fracture during treatment does not necessarily mean treat-ment is effective. Therefore, surrogate indices of treatment There are very few data on the use of glucocorticoids in efficacy are recommended.
younger men. In the reported randomized double-blind trials, In glucocorticoid-treated patients not receiving bone- the majority of men were over the age of 50 years, with none protective therapy, BMD measurements using DXA are of the trials reporting on subsets of younger men. As such, any recommended at baseline and at appropriate intervals there- recommendations that can be made are based on expert opin- after depending on the baseline level, the dose of GC, the ion. In men, therapy with a bisphosphonate is of benefit when disease for which it is given and the age and gender of compared to placebo in maintaining bone mass. No conclu- the patient. In patients receiving bone-protective therapy, sions may be drawn regarding reduction in fracture risks.
monitoring with BMD is recommended, the frequency ofwhich will depend on the same factors. The BMD mea- Premenopausal women surement precision error (the least significant change ateach skeletal site established for the laboratory) must be In general, premenopausal women on glucocorticoids are considered when interpreting serial assessments in order less susceptible to fracture than postmenopausal women.
to determine whether the change is real . How- However, a small study suggested that glucocorticoid-treated ever, it should be emphasised that improvement in BMD premenopausal women fractured at higher BMD than their during treatment with anti-resorptive drugs accounts for a postmenopausal counterparts Vertebral fractures in pre- predictable but small part of the observed reduction in menopausal women treated with glucocorticoids may be as- the risk of vertebral fracture in postmenopausal osteopo- sociated with lower cortical bone mass than in those without a rosis [and the relationship between BMD changes fracture ]. Independently of BMD, elevated BTMs might and fracture risk reduction in patients treated for identify cases with prevalent vertebral fracture ]. Factors glucocorticoid-induced osteoporosis is unknown. Poor other than glucocorticoids that help to identify premenopausal adherence to therapy, failure to respond to therapy or women at increased fracture risk are prior fractures , previously unrecognised secondary causes of osteoporo- low BMD [family history of osteoporosis [ sis should be searched for in patients with documented low BMI or low weight , ], age ], age at BMD loss .
menarche ], major depression  and alcohol Table 7 Recommendations formonitoring during glucocorti- Grading of evidence Assessment of adherence to therapy, including calcium and vitamin D, at each visit Measurement of BMD at appropriate intervals Annual height measurement Vertebral fracture assessment by X-ray or DXA if fracture is suspected Measurement of serum PINP after 3 months of teriparatide therapy intake [In those on glucocorticoids, sustained high doses postmenopausal women treated with teriparatide and may increase the risk of fracture ].
alendronate, respectively, with corresponding figures fornon-vertebral fracture of nine and six . However,fracture was not a primary end point of this study, and Management of glucocorticoid-induced osteoporosis in premenopausal women and men aged 50 years or less the small number of fractures in premenopausal women • Premenopausal women and younger men have a lower risk of fracture and younger men precludes any conclusions about the than older individuals.
relative anti-fracture efficacy of alendronate and teripara- • Data on the effects of pharmacological interventions in this tide in these populations.
population are sparse, particularly with regard to fracture risk.
In studies limited to premenopausal women, alendronate • Bone-protective therapy may be appropriate in some premenopausal was more effective in maintaining BMD compared to either women and younger men, particularly in individuals with a previous calcitriol or alfacalcidol [Etidronate was also history of fracture or receiving high doses of glucocorticoids.
found to be more effective at preventing bone loss than Caution is advised in the use of bisphosphonates in women of childbearing age.
alfacalcidol in premenopausal women treated with gluco-corticoids [In patients with systemic lupus eryth- Men and premenopausal women on oral glucocorticoids ematosus (SLE) treated with high-dose glucocorticoids, of are less likely to undergo BMD testing and to receive bone- whom 70% of women were premenopausal, risedronate was protective therapy than postmenopausal women , pos- of benefit in preventing bone loss at the lumbar spine sibly because indications for the prevention of bone loss and In a study of glucocorticoid-treated patients with chronic fractures are not as clearly defined as in postmenopausal kidney disease in which women in the study were predom- women. There are a few treatment studies that are confined inantly premenopausal, risedronate was effective in prevent- to premenopausal women; however, in general, the studies ing bone loss at the lumbar spine when compared to active that have been done include premenopausal women as a vitamin D In another small study of predominantly subset of the overall study, and there are very few fracture premenopausal women with renal disease, the combination data from which conclusions may be drawn. As a result, the of risedronate and alfacalcidol appeared to be of greater available evidence is based on BMD data.
benefit than either alone . In studies limited to calcitriol In large randomized controlled trials in which subsets of compared to calcium and vitamin D [and vitamin D premenopausal women and men were studied, therapy with compared to placebo , no significant benefit of alendronate [risedronate [and etidronate [has calcitriol over calcium and vitamin D or vitamin D over been reported to prevent bone loss at the lumbar spine when placebo was demonstrated. In a small study of inhaled compared to placebo. In the comparative study of zoledronic and intermittent oral glucocorticoids, which did contain acid versus risedronate ], a subset analysis of men in the premenopausal women, calcitriol did not offer any benefit trial demonstrated significantly greater increases in lumbar spine BMD at 1 year in men treated with zoledronic acid In a small study of hypogonadal women with SLE, hor- than in those treated with risedronate, both in the prevention mone replacement therapy was more effective than calcitriol and treatment subpopulations. Total hip BMD increased in preventing bone loss In another small study of significantly in men treated with zoledronic acid, although alfacalcidol compared to placebo alfacalcidol was of the treatment difference was not significantly greater than benefit in maintaining bone mass.
that seen in risedronate-treated men . In a post hoc Despite the lack of evidence for fracture reduction in analysis in premenopausal women included in this trial, glucocorticoid-treated premenopausal women, bone- significantly greater increases in total hip, but not lumbar protective therapy may be appropriate in some cases, particu- spine, BMD were seen at 12 months in women treated with larly in patients treated with high doses of glucocorticoids and zoledronic acid when compared with those treated with in those with a previous history of fracture. Long-term use of risedronate .
bisphosphonates and the potential for side effects remain a Teriparatide has been shown to result in larger increases concern. Caution is advised to women of childbearing age as in BMD than alendronate in premenopausal women and bisphosphonates cross the placenta and may affect the skeletal men with GIO . Radiographic vertebral fractures were health of the developing fetus (see ).
not seen in any premenopausal women or men treated withteriparatide and were present in four men, but no premeno- We are grateful to Amanda Sherwood and Heidi- pausal women, treated with alendronate. Non-vertebral frac- Mai Warren from the European Calcified Tissue Society and Judy tures occurred in two premenopausal women and one man Stenmark from the International Osteoporosis Foundation, for admin-istrative support. This paper has been consulted by the IOF Committee treated with teriparatide and two men, but no premenopausal of National Societies and the following associations: EFFORT, AO women, treated with alendronate. In comparison, radio- Trauma, International Society of Orthopaedic Surgery and Traumatol- graphic vertebral fractures were seen in one and six ogy, Endocrine Society, International Society of Endocrinology, AACE, ILAR, EULAR, ACR, International Menopause Society, Inter- national Association of Gerontology and Geriatrics, European UnionGeriatric Medicine Society, American Geriatrics Society and ASBMR.
1. Compston JE (2010) Management of glucocorticoid-induced Conflict of interest Adachi J.D. is consultant/speaker for Amgen, Eli osteoporosis. Nature Rev Rheumatol 6:82–88 Lilly, GSK, Merck, Novartis, Pfizer, Procter & Gamble, Roche, Sanofi 2. American College of Rheumatology ad hoc Committee on Aventis and Warner Chilcott and received grants for clinical trials from Glucocorticoid-induced Osteoporosis (2001) Recommendations Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, for the prevention and treatment of glucocorticoid-induced oste- Procter & Gamble, Sanofi Aventis, Roche and Warner Chilcott.
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the diagnosis and management of osteoporosis in Canada. CMAJ Cooper C. receives lecture fees and consultancy from ABBH, Amgen, Eli Lilly, GSK/Roche, MSD, Novartis, Nycomed and Servier.
5. Devogelaer JP, Goemaere S, Boonen S, Body JJ, Kaufman JM, Diez Perez A. receives honoraria as consultant or speaker from Amgen, Reginster JY, Rozenberg S, Boutsen Y (2006) Evidence-based Eli Lilly and MSD as well as research funds from Alliance of Bone guidelines for the prevention and treatment of glucocorticoid- Health and Servier.
induced osteoporosis: a consensus document of the Belgian Bone Eastell R. is a member of the Procter & Gamble National Advisory Club. Osteoporos Int 17:8–19 Board, Medical Research Council, European Calcified Tissue Society, 6. Geusens PP, Lems WF, Verhaar HJ, Leusink G, Goemaere S, Biobank MSK Advisory Board; a consultant for Amgen, AstraZeneca, Zmierczack H, Compston JE (2006) Review and evaluation of the GlaxoSmithKline, Medtronics, Nastech, Nestle, Fonterra Brands, Dutch guidelines for osteoporosis. J Eval Clin Pract 12:539–548 Novartis, Ono Pharma, Osteologix, Pfizer, Eli Lilly, Sanofi Aventis, 7. Gourlay M, Franceschini N, Sheyn Y (2007) Prevention and Tethys, Unilever, Unipath, Inverness Medical, Johnson & Johnson, treatment strategies for glucocorticoid-induced osteoporosis. Clin SPD and MSD and IDS; received grants from AstraZeneca, Unilever, Rheumatol 26:144–153 Amgen, Department of Health, National Institute for Health Research, 8. Hoes JN, Jacobs JW, Boers M, Boumpas D, Buttgereit F, Caeyers Sheffield Teaching Hospitals Trust, Queen Mary University of London, N, Choy EH, Cutolo M, Da Silva JA, Esselens G, Guillevin L, Procter & Gamble, Unipath Limited, Novartis, Medical Research Council Hafstrom I, Kirwan JR, Rovensky J, Russell A, Saag KG, Svensson UK, Arthritis Research UK, Nestle Foundation and Sanofi Aventis; B, Westhovens R, Zeidler H, Bijlsma JW (2007) EULAR evidence- received payment for lectures including service on speakers based recommendations on the management of systemic glucocor- bureaus from Takeda, Eli Lilly, Amgen, National Osteoporosis ticoid therapy in rheumatic diseases. Ann Rheum Dis 66:1560– Foundation, Procter & Gamble, GlaxoSmithKline Nutrition and Roche; received travel, accommodations or meeting expenses from Novar- 9. Nawata H, Soen S, Takayanagi R, Tanaka I, Takaoka K, Fukunaga tis, Procter & Gamble, GlaxoSmithKline Nutrition, Fonterra Brands, M, Matsumoto T, Suzuki Y, Tanaka H, Fujiwara S, Miki T, Sagawa Amgen, AstraZeneca, Medtronics, Unilever, Ono Pharma, Servier, Tethys, A, Nishizawa Y, Seino Y, Subcommittee to Study Diagnostic Cri- Eli Lilly, SPD and International Osteoporosis Foundation.
teria for Glucocorticoid-Induced Osteoporosis (2005) Guidelines on Kanis J.A. receives consulting fees, paid advisory boards, lecture the management and treatment of glucocorticoid-induced osteopo- fees and/or grant support from the majority of companies concerned rosis of the Japanese Society for Bone and Mineral Research with skeletal metabolism.
(2004). J Bone Miner Metab 23:105–109 Langdahl B. is a member of the advisory board of Amgen, Lilly, 10. National Osteoporosis Foundation (2008) Clinician's guide to Nycomed and MSD and the speakers bureau of Lilly, Amgen and prevention and treatment of osteoporosis. National Osteoporosis MSD; and received research funding from Lilly, Novartis, MSD and Foundation, Washington, DC, www.nof.org. Accessed 15 August McCloskey E. receives research funding and/or advisory board and/ 11. Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, or speaker's fees from the following: Amgen, AstraZeneca, GSK, Chen W, Curtis JR, Furst DE, McMahon M, Patkar NM, Hologic, Innovus, Lilly, MSD, Novartis, Pfizer, Roche, Servier, Tethys Volkmann E, Saag KG (2010) American College of Rheu- and Warner Chilcott.
matology 2010 recommendations for the prevention and Napoli N. receives consultancy and lecture fees from MSD.
treatment of glucocorticoid-induced osteoporosis. Arth Care Ralston S. received research grants from Amgen and his employer Res 62:1515–1526 received consultancy income from Amgen, Merck and Novartis.
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osteoporosis. The Global Longitudinal Study of Osteoporosis in Compston J.E. receives consultancy fees and lecture fees, and/or Women (GLOW). Bone 49:493–498 received grant support from the Alliance for Better Bone Health, Amgen, 13. van Staa TP, Leufkens HG, Cooper C (2002) The epidemiology Eli Lilly, GlaxoSmithKline, Medtronic, MSD, Novartis, Nycomed, of corticosteroid-induced osteoporosis: a meta-analysis. Osteo- Procter & Gamble, Sanofi Aventis, Servier and Warner Chilcott.
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The American Journal of Pathology, Vol. 176, No. 4, April 2010 Copyright © American Society for Investigative Pathology Cardiovascular, Pulmonary and Renal Pathology Therapeutic Targeting of Classical and LectinPathways of Complement Protects fromIschemia-Reperfusion-Induced Renal Damage Giuseppe Castellano,* Rita Melchiorre,* of classical and lectin pathways of complement in a