Need help?

800-5315-2751 Hours: 8am-5pm PST M-Th;  8am-4pm PST Fri
Medicine Lakex

Osteoporos 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.
oporosis: 2001 update. Arthritis Rheum 44:1496–1503 Agnusdei D. is a stock holder and employee of Eli Lilly and 3. Royal College of Physicians (2002) Glucocorticoid-induced osteoporosis. Guidelines on prevention and treatment. Bone Bilezikian J.P. receives consultancies and speaker fees for Amgen, and Tooth Society of Great Britain, National Osteoporosis Lilly, Merck and Novartis; consultancies for Radius Pharmaceuticals, Society and Royal College of Physicians. Royal College of NPS Pharmaceuticals and GSK; and research support from NPS Physicians, London 4. Brown JP, Josse RG, Scientific Advisory Council of the Osteo- Boonen S. receives research support and/or consulting fees from porosis Society of Canada (2002) Clinical practice guidelines for Amgen, Merck, Novartis, Sanofi Aventis and Warner Chilcott.
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, 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.
12. Díez-Pérez A, Hooven FH, Adachi JD, Adami S, Anderson FA, Silverman S. is a member of the speaker's bureau for Amgen, Lilly, Boonen S, Chapurlat R, Compston JE, Cooper C, Delmas P, Pfizer and Roche Pharmaceuticals; a consultant for Amgen, Lilly, Greenspan SL, LaCroix AZ, Lindsay R, Netelenbos JC, Pfeilschifter Novartis, Pfizer, Roche Pharmaceuticals, Roche Diagnostics and J, Roux C, Saag KG, Sambrook P, Silverman S, Siris ES, Watts NB, Warner Chilcott; and received research support from Alliance for Nika G, Gehlbach SH (2011) Regional differences in treatment for Better Bone Health, Lilly and Pfizer.
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.
poros Int 13:777–787 Borgstrom F., Hofbauer L., Lekamwasam S., Lesnyak O., Lorenc 14. van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C R., Messina O.D., Obermayer-Pietsch B., Stepan J., Sambrook P., Sosa (2000) Oral corticosteroids and fracture risk: relationship to daily M., Suppan G. and Wahl D.A. declare no conflict of interest.
and cumulative doses. Rheumatol Phys Med 39:1383–1389 15. van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C 31. Kim HJ, Zhao H, Kitaura H, Bhattacharyya S, Brewer JA, Muglia (2000) Use of oral corticosteroids and risk of fractures. J Bone LJ, Ross FP, Teitelbaum SL (2006) Glucocorticoids suppress Miner Res 15:933–1000 bone formation via the osteoclast. J Clin Invest 116:2152– 16. Hoes JN, Jacobs JW, Hulsmans HM, De Nijs RN, Lems WF, Bruyn GA, Geusens PP, Bijlsma JW (2010) High incidence rate of verte- 32. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, bral fractures during chronic prednisone treatment, in spite of Gavaghan DJ, McQuay HJ (1996) Assessing the quality of bisphosphonate or alfacalcidol use. Extension of the alendronate reports of randomized clinical trials: is blinding necessary? Con- or alfacalcidol in glucocorticoid-induced osteoporosis-trial. Clin trol Clin Trials 17:1–12 Exp Rheumatol 28:354–359 33. World Health Organization (2007) Assessment of osteoporosis at the 17. Kanis JA, Johansson H, Oden A, Johnell O, de Laet C, Melton LJ primary health care level. At: III, Tenenhouse A, Reeve J, Silman AJ, Pols HA, Eisman JA, . Accessed 15 August 2011 McCloskey EV, Mellstrom D (2004) A meta-analysis of prior 34. Kanis JA on behalf of the World Health Organization Scientific corticosteroid use and fracture risk. J Bone Miner Res 19:893– Group (2008) Assessment of osteoporosis at the primary health- care level. Technical Report. WHO Collaborating Centre, Uni- 18. van Staa TP, Leufkens HG, Cooper C (2001) Use of inhaled versity of Sheffield, UK. Available at: corticosteroids and risk of fractures. J Bone Miner Res 16:581– . Accessed 15 August 2011 35. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey EV 19. de Vries F, Bracke M, Leufkens HG, Lammers JW, Cooper C, (2008) FRAX™ and the assessment of fracture probability in van Staa TP (2007) Fracture risk with intermittent high-dose oral men and women from the UK. Osteoporos Int 19:385–397 glucocorticoid therapy. Arthritis Rheum 56:208–214 36. Kanis JA, Oden A, Johnell O, Johansson H, De Laet C, Brown JP, 20. Canalis E, Mazziotti G, Giustina A, Bilezikian JP (2007) Burckhardt P, Cooper C, Christiansen C, Cummings S, Eisman Glucocorticoid-induced osteoporosis: pathophysiology and ther- JA, Fujiwara S, Glüer C, Goltzman D, Hans D, Krieg MA, La apy. Osteoporos Int 18:1319–1328 Croix A, McCloskey E, Mellstrom D, Melton LJ 3rd, Pols H, 21. Hofbauer LC, Rauner M (2009) Minireview: live and let die: Reeve J, Sanders K, Schott AM, Silman A, Torgerson D, van Staa molecular effects of glucocorticoids on bone cells. Mol Endocri- T, Watts NB, Yoshimura N (2007) The use of clinical risk factors nol 23:1525–1531 enhances the performance of BMD in the prediction of hip and 22. van de Berg BC, Malghem J, Lecouvet FE, Devogelaer JP, osteoporotic fractures in men and women. Osteoporos Int Maldague B, Houssiau FA (1999) Fat conversion of femoral marrow in glucocorticoid-treated patients: a cross-sectional and 37. Kanis JA, Johnell O, De Laet C, Jonsson B, Oden A, longitudinal study with magnetic resonance imaging. Arthritis Oglesby A (2002) International variations in hip fracture Rheum 42:1405–1411 probabilities: implications for risk assessment. J Bone Miner 23. Mak W, Shao X, Dunstan CR, Seibel MJ, Zhou H (2009) Bi- Res 17:1237–1244 phasic glucocorticoid-dependent regulation of Wnt expression 38. Association Suisse contre l‘Ostéoporose (2010) Ostéoporose: and its inhibitors in mature osteoblastic cells. Calcif Tissue Int Recommandations 2010. ASCO 24. Ohnaka K, Taniguchi H, Kawate H, Nawata H, Takayanagi R Accessed 15 August 2011 (2004) Glucocorticoid enhances the expression of dickkopf-1 in 39. Socialstyrelsen (2010) Nationella riktlinjer för rörelseorganens human osteoblasts: novel mechanism of glucocorticoid-induced sjukdomar 2010 - stöd för styrning och ledning. Preliminär ver- osteoporosis. Biochem Biophys Res Commun 21:259–264 sion. Artikelnr 2010-11-15. Published at .
25. Wang FS, Ko JY, Yeh DW, Ke HC, Wu HL (2008) Modulation of Accessed 15 August 2011.
Dickkopf-1 attenuates glucocorticoid induction of osteoblast ap- 40. Compston JE, Cooper A, Cooper C, Francis R, Kanis JA, Marsh optosis, adipocytic differentiation, and bone mass loss. Endocri- D, McCloskey EV, Reid DM, Selby P, Wilkins M, National nology 149:1793–1801 Osteoporosis Guideline Group (NOGG) (2009) Guidelines for 26. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC (1998) Inhi- the diagnosis and management of osteoporosis in postmenopausal bition of osteoblastogenesis and promotion of apoptosis of osteo- women and men from the age of 50 years in the UK. Maturitas blasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 102:274–282 41. Czerwinski E, Kanis JA, Trybulec B, Johansson H, Borowy P, 27. Cherian PP, Xia X, Jiang JX (2008) Role of gap junction, hemi- Osieleniec J (2009) The incidence and risk of hip fracture in channels, and connexin 43 in mineralizing in response to inter- Poland. Osteoporos Int 20:1363–1368 mittent and continuous application ofparathyroid hormone. Cell 42. Dawson-Hughes B (2008) A revised clinician's guide to the Commun Adhes 15:43–54 prevention and treatment of osteoporosis. J Clin Endocrinol 28. Plotkin LI, Lezcano V, Thostenson J, Weinstein RS, Manolagas Metab 93:2463–2465 SC, Bellido T (2008) Connexin 43 is required for the anti- 43. Fujiwara S, Nakamura T, Orimo H, Hosoi T, Gorai I, Oden A, apoptotic effect of bisphosphonates on osteocytes and osteoblasts Johansson H, Kanis JA (2008) Development and application of a in vivo. J Bone Miner Res 23:1712–1721 Japanese model of the WHO fracture risk assessment tool 29. Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, (FRAX™). Osteoporos Int 19:429–448 Spelsberg TC, Khosla S (1999) Stimulation of osteoprote- 44. Kanis JA, Burlet N, Cooper C, Delmas PD, Reginster JY, Borgstrom gerin ligand and inhibition of osteoprotegerin production by F, Rizzoli R, European Society for Clinical and Economic Aspects of glucocorticoids in human osteoblastic lineage cells: potential para- Osteoporosis and Osteoarthritis (ESCEO) (2008) European guidance crine mechanisms of glucocorticoid-induced osteoporosis. Endocri- for the diagnosis and management of osteoporosis in postmenopaus- nology 140:4382–4389 al women. Osteoporos Int 19:399–428 30. Swanson C, Lorentzon M, Conaway HH, Lerner UH (2006) Glu- 45. Kanis JA, McCloskey EV, Johansson H, Strom O, Borgstrom F, cocorticoid regulation of osteoclast differentiation and expression of Oden A, National Osteoporosis Guideline Group (2008) Case receptor activator of nuclear factor-kappaB (NF-kappaB) ligand, finding for the management of osteoporosis with FRAX®— osteoprotegerin, and receptor activator of NF-kappaB in mouse assessment and intervention thresholds for the UK. Osteoporos Int calvarial bones. Endocrinology 147:3613–3622 19:1395–1408, Erratum 2009 Osteoporos Int 20: 499-502 46. Lippuner K, Johansson H, Kanis JA, Rizzoli R (2010) FRAX® the diagnosis, prevention and treatment of osteoporosis. Reumatismo assessment of osteoporotic fracture probability in Switzerland.
Osteoporos Int 21:381–390 60. González Macias J, Guañabens N, Gomez Alonso C, del Rio 47. Neuprez A, Johansson H, Kanis JA, McCloskey EV, Odén A, Barquero L, Munoz Torres M, Delgado M, Perez Edo L, Bruyère O, Hiligsmann M, Devogelaer JP, Kaufman JM, Bernardino Diaz Lopez J, Jodar Gimeno E, Hawkins Carranza F, Reginster JY (2009) Rationalisation du remboursement des Comité de Redacción, en representación del Comité de Expertos de médicaments de l'ostéoporose: de la mesure isolée de la la SEIOMM para la elaboración de las Guías (2008) Practice guide- densité osseuse à l'intégration des facteurs cliniques de risque lines for postmenopausal, steroid-induced and male osteoporosis.
fracturaire. Validation de l'algorithme FRAX®. La Revue Médicale Spanish Society for Bone and Mineral Research. Rev Clin Esp 208 de Liège 64:612–619 48. Papaioannou A, Morin S, Cheung AM, Atkinson S, Brown JP, 61. Dawson-Hughes B, Tosteson AN, Melton LJ, Baim S, Favus MJ, Feldman S, Hanley DA, Hodsman A, Jamal SA, Kaiser SM, Khosla S, Lindsay RL, National Osteoporosis Foundation Guide Kvern B, Siminoski K, Leslie WD, Scientific Advisory Council Committee (2008) Implications of absolute fracture risk assess- of Osteoporosis Canada (2010) 2010 clinical practice guidelines ment for osteoporosis practice guidelines in the USA. Osteoporos for the diagnosis and management of osteoporosis in Canada: summary. CMAJ 182:1864–1873 62. Kanis JA, Borgstrom F, Zethraeus N, Johnell O, Oden A, Jonsson 49. Kanis JA, Johnell O, Committee of Scientific Advisors of the B (2005) Intervention thresholds for osteoporosis in the UK.
International Osteoporosis Foundation (2005) Requirements for DXA for the management of osteoporosis in Europe. Osteoporos 63. European Community (1998) Report on osteoporosis in the European Community. 1998. EC, Strasbourg 50. Kanis JA, McCloskey E, Johansson H, Oden A, Leslie WD 64. Royal College of Physicians (1999) Osteoporosis: clinical guide- (2012) FRAX® with and without bone mineral density. Calcif lines for the prevention and treatment. Royal College of Physi- Tissue Int 90:1–13 51. Leib ES, Saag KG, Adachi JD, Geusens PP, Binkley N, 65. Kanis JA, Delmas P, Burckhardt P, Cooper C, Torgerson D, McCloskey EV, Hans DB, FRAX(®) Position Development European Foundation for Osteoporosis and Bone Disease Conference Members (2011) The impact of the use of glucocorti- (1997) Guidelines for diagnosis and management of osteoporosis.
coids on the estimate by FRAX of the 10 year risk of fracture. J Clin Osteoporos Int 7:390–406 Densitom 14:212–219 66. Strom O, Borgstrom F, Kanis JA, Compston JE, Cooper C, 52. van Staa TP, Abenhaim L, Cooper C, Zhang B, Leufkens HG McCloskey E, Jonsson B (2011) Osteoporosis; burden, health (2001) Public health impact of adverse bone effects of oral care provision and opportunities in the EU. A report prepared in corticosteroids. Br J Clin Pharmacol 51:601–607 collaboration with the International Osteoporosis Foundation 53. van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C (IOF) and the European Federation of Pharmaceutical Industry (2000) Fracture and oral corticosteroids: relationship to daily and Associations (EFPIA). Arch Osteoporos 6:59–155 cumulative dose. Rheumatol 39:1383–1389 67. Johansson H, Kanis JA, Oden A, Johnell O, Compston J, 54. Kanis JA, Johansson H, Oden A, McCloskey E (2011) Guidance McCloskey EV (2011) A comparison of case finding strategies for the adjustment of FRAX according to the dose of glucocorticoids.
in the UK for the management of hip fractures. Osteoporos Int Osteoporos Int 22:809–816 55. Kanis JA, Hans D, Cooper C, Baim S, Bilezikian JP, Binkley N, 68. Leslie WD, Morin S, Lix LM, Johansson H, Oden A, McCloskey Cauley JA, Compston JE, Dawson-Hughes B, El-Hajj Fuleihan E, Kanis JA, Manitoba Bone Density Program (2012) Fracture G, Johansson H, Leslie WD, Lewiecki EM, Luckey M, Oden A, risk assessment without bone density measurement in routine Papapoulos SE, Poiana C, Rizzoli R, Wahl DA, McCloskey EV, clinical practice. Osteoporos Int 23:75–85 Task Force of the Frax Initiative (2011) Interpretation and use of 69. Johansson H, Kanis JA, Oden A, Johnell O, McCloskey E (2009) FRAX in clinical practice. Osteoporos Int 22:2395–2411 BMD, clinical risk factors and their combination for hip fracture 56. Leslie WD, Lix LM, Johansson H, Oden A, McCloskey E, Kanis prevention. Osteoporos Int 20:1675–1682 JA (2011) Spine-hip discordance and fracture risk assessment: a 70. Johansson H, Oden A, Johnell O, Jonsson B, De Laet C, Oglesby physician-friendly FRAX enhancement. Osteoporos Int 22:839– A, McCloskey EV, Kayan K, Jalava T, Kanis JA (2004) Optimi- sation of BMD measurements to identify high risk groups for 57. Nawata H, Soen S, Takayanagi R, Tanaka I, Takaoka K, Fukunaga treatment—a test analysis. J Bone Miner Res 19:906–913 M, Matsumoto T, Suzuki Y, Tanaka H, Fujiwara S, Miki T, Sagawa 71. Kanis JA, Adams J, Borgström F, Cooper C, Jönsson B, Preedy A, Nishizawa Y, Seino Y (2005) Guidelines on the management and D, Selby P, Compston J (2008) The cost-effectiveness of alendronate treatment of glucocorticoid-induced osteoporosis of the Japanese in the management of osteoporosis. Bone 42:4–15 Society for Bone and Mineral Research (2004). J Bone Miner 72. Leslie WD, Lix LM, Majumdar SR, Johansson H, Oden A, Metab 23:105–109 McCloskey E, Kanis JA, Manitoba Bone Density Program 58. Agence Française de Sécurité Sanitaire des Produits de Santé (2011) High fracture probability with FRAX® usually indicates (2006) Traitement medicamenteux de l'osteoporose post- densitometric osteoporosis: implications for clinical practice.
ménopausique – Recommandations Osteoporos Int. doi: 73. Kanis JA, Stevenson M, McCloskey EV, Davis S, Lloyd-Jones M (2007) Glucocorticoid-induced osteoporosis: a systematic review and cost-utility analysis. Health Technol Assess 11:1–256 Accessed 08 November 2011.
74. Tosteson AN, Melton LJr, Dawson-Hughes B, Baim S, Favus MJ, 59. Adami S, Bertoldo F, Brandi M-L, Cepollaro C, Filipponi P, Fiore Khosla S, Lindsay RL, National Osteoporosis Foundation Guide E, Frediani B, Giannini S, Gonnelli S, Isaia GC, Luisetto G, Committee (2008) Cost-effective osteoporosis treatment thresholds: Mannarino E, Marcocci C, Masi L, Mereu C, Migliaccio S, the United States perspective. Osteoporos Int 19:437–447 Minisola S, Nuti R, Rini G, Rossini M, Varenna M, Ventura L, 75. Middleton ET, Gardiner ED, Steel SA (2009) Which women Bianchi G, Società Italiana dell'Osteoporosi, del Metabolismo should be selected for vertebral fracture assessment? Comparing Minerale e delle Malattie dello Scheletro (2009) Guidelines for different methods of targeting VFA. Calcif Tissue Int 85:203–210 76. Compston J, Reid DM, Boisdron J, Brandi ML, Burlet N, Cahall 89. Roux C, Oriente P, Laan R, Hughes RA, Ittner J, Goemaere S, Di D, Delmas PD, Dere W, Devogelaer JP, Fitzpatrick LA, Flamion Munno O, Pouillès JM, Horlait S, Cortet B (1998) Randomized B, Goel N, Korte S, Laslop A, Mitlak B, Ormarsdottir S, Ringe J, trial of effect of cyclical etidronate in the prevention of Rizzoli R, Tsouderos Y, van Staa T, Reginster JY, Group for the corticosteroid-induced bone loss. J Clin Endocrinol Metab Respect of Ethics and Excellence in Science (2008) Recommen- dations for the registration of agents for prevention and treatment 90. Skingle SJ, Crisp AJ (1994) Increased bone density in patients on of glucocorticoid-induced osteoporosis: an update from the steroids with etidronate. Lancet Infect Dis 344:543–544 Group for the Respect of Ethics and Excellence in Science.
91. Struys A, Snelder AA, Mulder H (1995) Cyclical etidronate Osteoporos Int 19:1247–1250 reverses bone loss of the spine and proximal femur in patients 77. Adachi JD, Saag KG, Delmas PD, Liberman UA, Emkey RD, with established corticosteroid-induced osteoporosis. Am J Med Seeman E, Lane NE, Kaufman JM, Poubelle PE, Hawkins F, Correa-Rotter R, Menkes CJ, Rodriguez-Portales JA, Schnitzer 92. Cohen S, Levy RM, Keller M, Boling E, Emkey RD, Greenwald TJ, Block JA, Wing J, McIlwain HH, Westhovens R, Brown J, M, Zizic TM, Wallach S, Sewell KL, Lukert BP, Axelrod DW, Melo-Gomes JA, Gruber BL, Yanover MJ, Leite MO, Siminoski Chines AA (1999) Risedronate therapy prevents corticosteroid- KG, Nevitt MC, Sharp JT, Malice MP, Dumortier T, Czachur M, induced bone loss: a twelve month, multicenter, randomized, Carofano W, Daifotis AG (2001) Two-year effects of alendronate double-blind, placebo-controlled, parallel-group study. Arthritis on bone mineral density and vertebral fracture in patients receiving Rheum 42:2309–2318 glucocorticoids: a randomized, double-blind, placebo-controlled 93. Eastell R, Devogelaer J-P, Peel NFA, Chines AA, Bax DE, extension trial. Arthritis Rheum 44:202–211 Sacco-Gibson N, Nagant de Deuxchaisnes C, Russell RG (2000) 78. de Nijs RN, Jacobs JW, Lems WF, Laan RF, Algra A, Huisman Prevention of bone loss with risedronate in glucocorticoid-treated AM, Buskens E, de Laet CE, Oostveen AC, Geusens PP, Bruyn rheumatoid arthritis patients. Osteoporos Int 11:331–337 GA, Dijkmans BA, Bijlsma JW, Investigators STOP (2006) 94. Reid DM, Adami S, Devogelaer JP, Chines AA (2001) Risedronate Alendronate or alfacalcidol in glucocorticoid-induced osteoporo- increases bone density and reduces vertebral fracture risk within one sis. N Engl J Med 355:675–684 year in men on corticosteroid therapy. Calcif Tissue Int 69:242–247 79. Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere 95. Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderoth S, Thamsborg G, Liberman UA, Delmas PD, Malice MP, Czachur DH, Adami S, Eusebio RA, Devogelaer JP (2000) Efficacy and M, Daifotis AG (1998) Alendronate for the prevention and treat- safety of daily risedronate in the treatment of corticosteroid- ment of glucocorticoid-induced osteoporosis. Glucocorticoid- induced osteoporosis in men and women: a randomized trial.
Induced Osteoporosis Intervention Study Group. N Engl J Med European Corticosteroid-Induced Osteoporosis Treatment Study.
J Bone Miner Res 15:1006–1013 80. Stoch SA, Saag KG, Greenwald M, Sebba AI, Cohen S, Verbruggen 96. Wallach S, Cohen S, Reid DM, Hughes RA, Hosking DJ, Laan N, Giezek H, West J, Schnitzer TJ (2009) Once-weekly oral alendr- RF, Doherty SM, Maricic M, Rosen C, Brown J, Barton I, Chines onate 70 mg in patients with glucocorticoid-induced bone loss: a 12- AA (2000) Effects of risedronate treatment on bone density and month randomized, placebo-controlled clinical trial. J Rheumatol vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int 67:277–285 81. Yilmaz L, Ozpran K, Gündüz OH, Ucan H, Yücel M (2001) 97. Reid DM, Devogelaer JP, Saag K, Roux C, Lau CS, Reginster JY, Alendronate in rheumatoid arthritis patients treated with metho- Papanastasiou P, Ferreira A, Hartl F, Fashola T, Mesenbrink P, trexate and glucocorticoids. Rheumatol Int 20:65–69 Sambrook PN, HORIZON investigators (2009) Zoledronic acid 82. Adachi JD, Bensen WG, Brown J, Hanley D, Hodsman A, Josse and risedronate in the prevention and treatment of glucocorticoid- R, Kendler DL, Lentle B, Olszynski W, Ste-Marie LG, induced osteoporosis (HORIZON): a multicentre, double-blind, Tenenhouse A, Chines AA (1997) Intermittent etidronate double-dummy, randomised controlled trial. Lancet 373:1253– therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 337:382–387 98. Saag KG, Shane E, Boonen S, Marín F, Donley DW, Taylor KA, 83. Cortet B, Hachulla E, Barton I, Bonvoisin B, Roux C (1999) Dalsky GP, Marcus R (2007) Teriparatide or alendronate in Evaluation of the efficacy of etidronate therapy in preventing glucocorticoid-induced osteoporosis. N Engl J Med 357:2028– glucocorticoid-induced bone loss in patients with inflammatory rheumatic diseases. Rev Rheumatol 66:214–219 99. Saag KG, Zanchetta JR, Devogelaer JP, Adler RA, Eastell R, See 84. Geusens P, Dequecker J, Vanhoof J, Stalmans R, Boonen S, Joly K, Krege JH, Krohn K, Warner MR (2009) Effects of teriparatide J, Nijs J, Raus J (1998) Cyclical etidronate increases bone density versus alendronate for treating glucocorticoid-induced osteoporo- in the spine and hip of postmenopausal women receiving long sis: thirty-six-month results of a randomized, double-blind, con- term corticosteroid treatment. A double blind, randomised place- trolled trial. Arthritis Rheum 60:3346–3355 bo controlled study. Ann Rheum Dis 57:724–727 100. Lakatos P, Nagy Z, Kiss L, Horvath CS, Takacs I, Foldes J, Speer 85. Jenkins EA, Walker-Bone KE, Wood A, McCrae FC, Cooper C, G, Bossanyi A (2000) Prevention of corticosteroid-induced oste- Cawley MI (1999) The prevention of corticosteroid-induced bone oporosis by alfacalcidol. Z Rheumatol 59(suppl 1):48–52 loss with intermittent cyclical etidronate. Scand J Rheumatol 101. Reginster JY, Kuntz D, Verdickt W, Wouters M, Guillevin L, Menkes CJ, Nielsen K (1999) Prophylactic use of alfacalcidol 86. Jinnouchi Y (2000) Efficacy of intermittent etidronate therapy for in corticosteroid-induced osteoporosis. Osteoporos Int 9:75–81 corticosteroid-induced osteoporosis in patients with diffuse con- 102. Ringe JD, Cöster A, Meng T, Schacht E, Umbach R (1999) nective tissue disease. Kurume Med J 47:219–224 Treatment of glucocorticoid-induced osteoporosis with alfacalci- 87. Mulder H, Struys A (1994) Intermittent cyclical etidronate in the dol/calcium versus vitamin D/calcium. Calcif Tissue Int 65:337– prevention of corticosteroid-induced bone loss. Br J Rheumatol 103. Sambrook PN, Kotowicz M, Nash P, Styles CB, Naganathan V, 88. Pitt P, Li F, Todd P, Webber D, Pack S, Moniz C (1998) A double Henderson-Briffa KN, Eisman JA, Nicholson GC (2003) Preven- blind placebo controlled study to determine the effects of inter- tion and treatment of glucocorticoid-induced osteoporosis: a com- mittent cyclical etidronate on bone mineral density in patients on parison of calcitriol, vitamin D plus calcium, and alendronate plus long term oral corticosteroid treatment. Thorax 53:351–356 calcium. J Bone Miner Res 18:919–924 104. Yamada H (1989) Long-term effect of 1a-hydroxyvitamin D, 122. Buckley LM, Hillner BE (2003) A cost effectiveness analysis of calcium and thiazide administration on glucocorticoid-induced calcium and vitamin D supplementation, etidronate, and alendro- osteoporosis. Folia Endocrinol Jap 65:603–614 nate in the prevention of vertebral fractures in women treated with 105. Diamond T, McGuigan I, Schonell M, Levy S, Rae D (1997) A glucocorticoids. J Rheumatol 30:132–138 2 year open randomised controlled trial comparing calcitriol to 123. Solomon DH, Kuntz KM (2000) Should postmenopausal women cyclical etidronate for the treatment of glucocorticoid-induced with rheumatoid arthritis who are starting corticosteroid treatment osteoporosis. J Bone Miner Res 12:S311 be screened for osteoporosis? A cost-effectiveness analysis. Arthritis 106. Dykman TR, Haralson KM, Gluck OS, Murphy WA, Teitelbaum Rheum 43:1967–1975 SL, Hahn TJ, Hahn BH (1984) Effect of oral 1,25-dhydroxyvita- 124. van Staa TP, Geusens P, Zhang B, Leufkens HG, Boonen S, Cooper min D and calcium on glucocorticoid-induced osteopenia in C (2007) Individual fracture risk and the cost-effectiveness of patients with rheumatic diseases. Arthritis Rheum 27:1336–1343 bisphosphonates in patients using oral glucocorticoids. Rheumatol 107. Rittmaster RS, Bolognese M, Ettinger MP, Hanley DA, Hodsman AB, Kendler DL, Rosen CJ (2000) Enhancement of bone mass in 125. Ström O, Borgström F, Sen SS, Boonen S, Haentjens P, Johnell osteoporotic women with parathyroid hormone followed by O, Kanis JA (2007) Cost-effectiveness of alendronate in the alendronate. J Clin Endocrinol Metab 85:2129–2134 treatment of postmenopausal women in 9 European countries— 108. Morris HA, Need AG, O'Loughlin PD, Horowitz M, Bridges A, an economic evaluation based on the fracture intervention trial.
Nordin BE (1990) Malabsorption of calcium in corticosteroid- Osteoporos Int 18:1047–1061 induced osteoporosis. Calcif Tissue Int 46:305–308 126. Borgstrom F, Strom O, Coelho J, Johansson H, Oden A, McCloskey 109. Boutsen Y, Jamart J, Esselinckx W, Devogelaer J-P (2001) Pri- EV, Kanis JA (2010) The cost-effectiveness of risedronate in the mary prevention of glucocorticoid-induced osteoporosis with in- UK for the management of osteoporosis using the FRAX. Osteo- travenous pamidronate and calcium: a prospective controlled 1- poros Int 21:495–505 year study comparing a single infusion, an infusion given once 127. Rizzoli R, Akesson K, Bouxsein M, Kanis JA, Napoli N, Papapoulos every 3 months, and calcium alone. J Bone Miner Res 16:104–112 S, Reginster JY, Cooper C (2011) Subtrochanteric fractures after 110. Sambrook P, Birmingham J, Kelly P, Kempler S, Nguyen T, Pocock long-term treatment with bisphosphonates: a European Society on N, Eisman J (1993) Prevention of corticosteroid osteoporosis. A Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, comparison of calcium, calcitriol, and calcitonin. N Engl J Med and International Osteoporosis Foundation Working Group Report.
Osteoporos Int 22:373–390 111. Sambrook PN (2000) Corticosteroid osteoporosis: practical impli- 128. Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown cations of recent trials. J Bone Miner Res 15:1645–1649 TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster D, 112. Holick MF (2007) Optimal vitamin d status for the prevention Einhorn TA, Genant HK, Geusens P, Klaushofer K, Koval K, and treatment of osteoporosis. Drugs Aging 24:1017–1029 Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O'Keefe 113. Buckley LM, Leib ES, Cartularo KS, Vacek PM, Cooper SM R, Papapoulos S, Sen HT, van der Meulen MC, Weinstein RS, (1996) Calcium and vitamin D3 supplementation prevents bone Whyte M, American Society for Bone and Mineral Research loss in the spine secondary to low-dose corticosteroids in patients (2010) Atypical subtrochanteric and diaphyseal femoral fractures: with rheumatoid arthritis. A randomized, double-blind, placebo- report of a task force of the American Society for Bone and controlled trial. Ann Intern Med 125:961–968 Mineral Research. J Bone Miner Res 25:2267–2294 114. Amin S, LaValley MP, Simms RW, Felson DT (1999) The role of 129. Giusti A, Hamdy NA, Dekkers OM, Ramautar SR, Dijkstra S, vitamin D in corticosteroid-induced osteoporosis: a meta-analytic Papapoulos SE (2011) Atypical fractures and bisphosphonate approach. Arthritis Rheum 42:1740–1751 therapy: a cohort study of patients with femoral fracture with 115. Homik J, Suarez-Almazor ME, Shea B, Cranney A, Wells G, radiographic adjudication of fracture site and features. Bone Tugwell P (2000) Calcium and vitamin D for corticosteroid- induced osteoporosis. Cochrane Database Syst Rev 2:CD000952.
130. Park-Wyllie LY, Mamdani MM, Juurlink DN, Hawker GA, Gunraj 116. Richy F, Schacht E, Bruyere O, Ethgen O, Gourlay M, Reginster N, Austin PC, Whelan DB, Weiler PJ, Laupacis A (2010) JY (2005) Vitamin D analogs versus native vitamin D in prevent- Bisphosphonate use and the risk of subtrochanteric or femoral shaft ing bone loss and osteoporosis-related fractures: a comparative fractures in older women. JAMA 305:783–789 meta-analysis. Calcif Tissue Int 76:176–186 131. Schilcher J, Michaëlsson K, Aspenberg P (2011) Bisphosphonate 117. Abrahamsen B, Sahota O (2011) Do calcium plus vitamin D use and atypical fractures of the femoral shaft. N Engl J Med supplements increase cardiovascular risk? BMJ 342:d2080 118. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, 132. Wang Z, Bhattacharyya T (2011) Trends in incidence of subtro- Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones chanteric fragility fractures and bisphosphonate use among the G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA (2011) The US elderly, 1996-2007. J Bone Miner Res 26:553–560 2011 report on dietary reference intakes for calcium and vitamin 133. Armamento-Villareal R, Napoli N, Diemer K, Watkins M, Civitelli D from the Institute of Medicine: what clinicians need to know. J R, Teitelbaum S, Novack D (2009) Bone turnover in bone biopsies Clin Endocrinol Metab 96:53–58 of patients with low-energy cortical fractures receiving bisphosph- 119. Fleurence RL, Iglesias CP, Johnson JM (2007) The cost- onates: a case series. Calcif Tissue Int 85:37–44 effectiveness of bisphosphonates for the prevention and treatment 134. Edwards MH, McCrae FC, Young-Min SA (2010) Alendronate- of osteoporosis: a structured review of the literautre. Pharmacoe- related femoral diaphysis fracture-what should be done to predict conomics 25:913–933 and prevent subsequent fracture of the contralateral side? Osteo- 120. Zethraeus N, Borgstrom F, Strom O, Kanis JA, Jonsson B (2007) poros Int 21:701–703 Cost-effectiveness of the treatment and prevention of osteoporo- 135. Goh SK, Yang KY, Koh JS, Wong MK, Chua SY, Chua DT, Howe sis–a review of the literature and a reference model. Osteoporos TS (2007) Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br 89:349–353 121. Beukelman T, Saag KG, Curtis JR, Kilgore ML, Pisu M (2010) 136. Ing-Lorenzini K, Desmeules J, Plachta O, Suva D, Dayer P, Peter Cost-effectiveness of multifaceted evidence implementation pro- R (2009) Low-energy femoral fractures associated with the long- grams for the prevention of glucocorticoid-induced osteoporosis.
term use of bisphosphonates: a case series from a Swiss univer- Osteoporos Int 21:1573–1584 sity hospital. Drug Saf 32:775–785 137. Kwek EB, Goh SK, Koh JS, Png MA, Howe TS (2008) An 153. Hodgson SF, Watts NB, Bilezikian JP, Clarke BL, Gray TK, emerging pattern of subtrochanteric stress fractures: a long-term Harris DW, Johnston CC, Kleerekoper M, Lindsay R, Luckey complication of alendronate therapy? Injury 39:224–231 MM, McClung MR, Nankin HR, Petak SM, Recker RR, AACE 138. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Osteoporosis Task Force (2003) American Association of Clini- Pak CY (2005) Severely suppressed bone turnover: a potential cal Endocrinologists medical guidelines for clinical practice for complication of alendronate therapy. J Clin Endocrinol Metab the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Pract 139. Visekruna M, Wilson D, McKiernan FE (2008) Severely sup- pressed bone turnover and atypical skeletal fragility. J Clin Endo- 154. Lenchik L, Kiebzak GM, Blunt BA (2002) What is the role of crinol Metab 93:2948–2952 serial bone mineral density measurements in patient manage- 140. Khan AA, Sándor GK, Dore E, Morrison AD, Alsahli M, Amin F, ment? J Clin Densitom 5:S29–38 Peters E, Hanley DA, Chaudry SR, Lentle B, Dempster DW, 155. Watts NB, Lewiecki EM, Bonnick SL, Laster AJ, Binkley N, Glorieux FH, Neville AJ, Talwar RM, Clokie CM, Mardini Blank RD, Geusens PP, Miller PD, Petak SM, Recker RR, Saag MA, Paul T, Khosla S, Josse RG, Sutherland S, Lam DK, Carmichael KG, Schousboe J, Siris ES, Bilezikian JP (2009) Clinical value of RP, Blanas N, Kendler D, Petak S, Ste-Marie LG, Brown J, Evans monitoring BMD in patients treated with bisphosphonates for AW, Rios L, Compston JE, Canadian Taskforce on Osteonecrosis of osteoporosis. J Bone Miner Res 24:1643–1646 the Jaw (2009) Bisphosphonate associated osteonecrosis of the jaw. J 156. Vasikaran S, Eastell R, Bruyère O, Foldes AJ, Garnero P, Rheumatol 36:478–490 Griesmacher A, McClung M, Morris HA, Silverman S, 141. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg Trenti T, Wahl DA, Cooper C, Kanis JA, IOF-IFCC Bone D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, Marker Standards Working Group (2011) Markers of bone McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, turnover for the prediction of fracture risk and monitoring of oste- Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, oporosis treatment: a need for international reference standards.
Watts N, Woo S-B, Shane E (2007) Bisphosphonate–associated Osteoporos Int 22:391–420 osteonecrosis of the jaw: report of a task force of the American 157. Eastell R, Krege JH, Chen P, Glass EV, Reginster JY (2006) Society for Bone and Mineral Research. J Bone Miner Res Development of an algorithm for using PINP to monitor treatment of patients with teriparatide. Curr Med Res Opin 142. Durie BG, Katz M, Crowley J (2005) Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 353:99–102 158. Kumagai S, Kawano S, Atsumi T, Inokuma S, Okada Y, Kanai Y, 143. Lazarovici TS, Yahalom R, Taicher S, Elad S, Hardan I, Yarom N Kaburaki J, Kameda H, Suwa A, Hagiyama H, Hirohata S, (2009) Bisphosphonate-related osteonecrosis of the jaws: a single- Makino H, Hashimoto H (2005) Vertebral fracture and bone center study of 101 patients. J Oral Maxillofac Surg 67:850–855 mineral density in women receiving high dose glucocorticoids 144. Woo SB, Hellstein JW, Kalmar JR (2006) Narrative [corrected] for treatment of autoimmune diseases. J Rheumatol 32:863–869 review: bisphosphonates and osteonecrosis of the jaws. Ann 159. Kaji H, Yamauchi M, Chihara K, Sugimoto T (2008) Glucocorti- Intern Med 144:753–761 coid excess affects cortical bone geometry in premenopausal, but 145. Patlas N, Golomb G, Yaffe P, Pinto T, Breuer E, Ornoy A (1999) not postmenopausal, women. Calcif Tissue Int 82:182–190 Transplacental effects of bisphosphonates on fetal skeletal ossifi- 160. Kaji H, Yamauchi M, Yamaguchi T, Sugimoto T (2010) Urinary cation and mineralization in rats. Teratology 60:68–73 deoxypyridinoline is a BMD-independent marker for prevalent 146. Losada I, Sartori L, Di Gianantonio E, Zen M, Clementi M, Doria vertebral fractures in postmenopausal women treated with gluco- A (2010) Bisphosphonates in patients with autoimmune rheumatic corticoid. Osteoporos Int 21:1585–1590 diseases: can they be used in women of childbearing age? Auto- 161. Honkanen R, Tuppurainen M, Kroger H, Alhava E, Puntila E immun Rev 9:547–552 (1997) Associations of early premenopausal fractures with sub- 147. Levy S, Fayez I, Taguchi N, Han JY, Aiello J, Matsui D, Moretti sequent fractures vary by sites and mechanisms of fractures.
M, Koren G, Ito S (2009) Pregnancy outcome following in utero Calcif Tissue Int 60:327–331 exposure to bisphosphonates. Bone 44:428–430 162. Hosmer WD, Genant HK, Browner WS (2002) Fractures before 148. Ornoy A, Wajnberg R, Diav-Citrin O (2006) The outcome of menopause: a red flag for physicians. Osteoporos Int 13:337–341 pregnancy following pre-pregnancy or early pregnancy alendro- 163. Horowitz M, Wishart JM, Bochner M, Need AG, Chatterton BE, nate treatment. Reprod Toxicol 22:578–579 Nordin BE (1988) Mineral density of bone in the forearm in 149. Baim S, Wilson CR, Lewiecki EM, Luckey MM, Downs RJ, premenopausal women with fractured wrists. BMJ 297:1314– Lentle BC (2005) Precision assessment and radiation safety for dual-energy X-ray absorptiometry: position paper of the Interna- 164. Armamento-Villareal R, Villareal DT, Avioli LV, Civitelli R (1992) tional Society for Clinical Densitometry. J Clin Densitom 8:371– Estrogen status and heredity are major determinants of premeno- pausal bone mass. J Clin Invest 90:2464–2471 150. Frost SA, Nguyen ND, Center JR, Eisman JA, Nguyen TV 165. Cohen A, Fleischer J, Freeby MJ, McMahon DJ, Irani D, Shane E (2009) Timing of repeat BMD measurements: development of (2009) Clinical characteristics and medication use among pre- an absolute risk-based prognostic model. J Bone Miner Res menopausal women with osteoporosis and low BMD: the expe- rience of an osteoporosis referral center. J Womens Health 18:79– 151. Gluer CC, Blake G, Lu Y, Blunt BA, Jergas M, Genant HK (1995) Accurate assessment of precision errors: how to measure 166. Moreira Kulak CA, Schussheim DH, McMahon DJ, Kurland E, the reproducibility of bone densitometry techniques. Osteoporos Silverberg SJ, Siris ES, Bilezikian JP, Shane E (2000) Osteopo- Int 19:1395–1408, Erratum 2009 Osteoporos Int 20: 499-502 rosis and low bone mass in premenopausal and perimenopausal women. Endocr Pract 6:296–304 152. Cummings SR, Karpf DB, Harris F, Genant HK, Ensrud K, 167. Peris P, Guañabens N, Martínez J, de Osaba M, Monegal A, LaCroix AZ, Black DM (2002) Improvement in spine bone Alvarez L, Pons F, Ros I, Cerdá D, Muñoz-Gómez J (2002) density and reduction in risk of vertebral fractures during Clinical characteristics and etiologic factors of premenopausal treatment with antiresorptive drugs. Am J Med 112:281– osteoporosis in a group of Spanish women. Semin Arthritis 168. Blum M, Harris SS, Must A, Phillips SM, Rand WM, premenopausal individuals with systemic autoimmune diseases.
Dawson-Hughes B (2001) Weight and body mass index at menar- J Rheumatol 31:163–166 che are associated with premenopausal bone mass. Osteoporos Int 179. Sato S, Ohosone Y, Suwa A, Yasuoka H, Nojima T, Fujii T, Kuwana M, Nakamura K, Mimori T, Hirakata M (2003) Effect 169. Hawker GA, Jamal SA, Ridout R, Chase C (2002) A clinical of intermittent cyclical etidronate therapy on corticosteroid in- prediction rule to identify premenopausal women with low bone duced osteoporosis in Japanese patients with connective tissue mass. Osteoporos Int 13:400–406 disease: 3 year follow-up. J Rheumatol 30:2673–2679 170. Sugiyama T, Suzuki S, Yoshida T, Suyama K, Tanaka T, Sueishi 180. Sato S, Takada T, Katsuki Y, Kimura N, Kaneko Y, Suwa A, M, Tatsuno I (2010) Incidence of symptomatic vertebral fractures Hirakata M, Kuwana M (2008) Longterm effect of intermittent in women of childbearing age newly treated with high-dose cyclical etidronate therapy on corticosteroid-induced osteoporosis glucocorticoid. Gend Med 7:218–229 in Japanese patients with connective tissue disease: 7-year fol- 171. Tatsuno I, Sugiyama T, Suzuki S, Yoshida T, Tanaka T, Sueishi lowup. J Rheumatol 35:142–146 M, Saito Y (2009) Age dependence of early symptomatic verte- 181. Mok CC, Tong KH, To CH, Siu YP, Ma KM (2008) Risedronate bral fracture with high-dose glucocorticoid treatment for collagen for prevention of bone mineral density loss in patients receiving vascular diseases. J Clin Endocrinol Metab 94:1671–1677 high-dose glucocorticoids: a randomized double-blind placebo- 172. Yirmiya R, Bab I (2009) Major depression is a risk factor for low controlled trial. Osteoporos Int 19:357–364 bone mineral density: a meta-analysis. Biol Psychiatry 66:423– 182. Fujii N, Hamano T, Mikami S, Nagasawa Y, Isaka Y, Moriyama T, Horio M, Imai E, Hori M, Ito T (2007) Risedronate, an 173. Solomon DH, Katz JN, Jacobs JP, La Tourette AM, Coblyn J effective treatment for glucocorticoid-induced bone loss in CKD (2002) Management of glucocorticoid-induced osteoporosis in patients with or without concomitant active vitamin D (PRIUS- patients with rheumatoid arthritis: rates and predictors of care in CKD). Nephrol Dial Transplant 22:1601–1607 an academic rheumatology practice. Arthritis Rheum 46:3136– 183. Kikuchi Y, Imakiire T, Yamada M, Saigusa T, Hyodo T, Kushiyama T, Higashi K, Hyodo N, Yamamoto K, Suzuki S, Miura S (2007) 174. Roux C, Reid DM, Devogelaer JP, Saag K, Lau CS, Reginster JY, Effect of risedronate on high-dose corticosteroid-induced bone loss Papanastasiou P, Bucci-Rechtweg C, Su G, Sambrook PN (2011) in patients with glomerular disease. Nephrol Dial Transplant Post hoc analysis of a single IV infusion of zoledronic acid versus daily oral risedronate on lumbar spine bone mineral density in 184. Lambrinoudaki I, Chan DT, Lau CS, Wong RW, Yeung SS, Kung different subgroups with glucocorticoid-induced osteoporosis.
AW (2000) Effect of calcitriol on bone mineral density in premeno- pausal Chinese women taking chronic steroid therapy. A randomized, 175. Langdahl BL, Marin F, Shane E, Dobnig H, Zanchetta JR, Maricic double blind, placebo controlled study. J Rheumatol 27:1759–1765 M, Krohn K, See K, Warner MR (2009) Teriparatide versus 185. Bernstein CN, Seeger LL, Anton PA, Artinian L, Geffrey S, alendronate for treating glucocorticoid-induced osteoporosis: Goodman W, Belin TR, Shanahan F (1996) A randomized, an analysis by gender and menopausal status. Osteoporos Int placebo-controlled trial of calcium supplementation for decreased bone density in corticosteroid-using patients with inflammatory 176. Yeap SS, Fauzi AR, Kong NC, Halim AG, Soehardy Z, Rahimah bowel disease: a pilot study. Aliment Pharmacol Ther 10:777–786 I, Chow SK, Goh EM (2008) A comparison of calcium, calcitriol, 186. McDonald CF, Zebaze RM, Seeman E (2006) Calcitriol does not and alendronate in corticosteroid-treated premenopausal patients prevent bone loss in patients with asthma receiving corticosteroid with systemic lupus erythematosus. J Rheumatol 35:2344–2347 therapy: a double-blind placebo-controlled trial. Osteoporos Int 177. Okada Y, Nawata M, Nakayamada S, Saito K, Tanaka Y (2008) Alendronate protects premenopausal women from bone loss and 187. Kung AW, Chan TM, Lau CS, Wong RW, Yeung SS (1999) fracture associated with high-dose glucocorticoid therapy. J Osteopenia in young hypogonadal women with systemic lupus Rheumatol 35:2249–2254 erythematosus receiving chronic steroid therapy: a randomized 178. Nakayamada S, Okada Y, Saito K, Tanaka Y (2004) Etidronate controlled trial comparing calcitriol and hormonal replacement prevents high dose glucocorticoid induced bone loss in therapy. Rheumatology (Oxford) 38:1239–1244


A universidade popular no brasil

Cómo referenciar este artículo / How to reference this article Gelabert Gual, Ll. (2014). Ideario y aportaciones metodológicas de Baltasar Bibiloni a la enseñanza musical en las Islas Baleares. Foro de Educación, 12(17), pp. 147-163. Ideario y aportaciones metodológicas de Baltasar Bibiloni a la enseñanza musical en

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