类固醇诱发的骨质疏松

Corticosteroid - Induced Osteoporosis,2012,Osteoporosis,Systemic skeletal diseaseLow bone massMicroarchitectural deterioration of bone tissueIncrease in bone fragility and fracture susceptibility,Clinical Burden of CIO,Most common form of drug-related osteoporosis in men and womenOccurs at any age, in both genders, across racesUp to 50% of patients on chronic steroid therapy sustain osteoporotic fractures and/or develop osteonecrosis,Corticosteroid-Induced Osteoporosis,Common, iatrogenic form of secondary osteoporosisAssociated with corticosteroid use in chronic, noninfectious medical conditionsAsthma - Nephrotic syndromeChronic lung disease- TransplantationRheumatologic disorders- etcInflammatory bowel disease,Clinical significant,- Increase bone loss and fracture : 6 Mo.- Trabecular cortical bone - 7.5 mg of prednisolone ( equivalent ) - Incidence of osteoporosis 30-50% - Vertebral fracture 30-35 % , hip fracture 50% - Rate of bone loss 2-4 % per year- Alternate day regimen , inhale steroids,Fracture Risk and Dose of Corticosteroids,Relative risk of fracture by dosages of corticosteroids of prednisolone. van Staa TP, et al, 1998.,0,1,2,3,4,5,6,2.5 mg/d,2.5-7.5 mg/d,7.5 mg/d,Relative risk of fracture,compared with control,Hip fracture,Vertebral fracture,CIO in Patients With Asthma,Relationship of percentage predicted bone density to duration of corticosteroid use in 44 corticosteroid-treated asthmatic patients. Schatz M, Dudl J, Zeiger RS, et al. Allergy Proc. 1993;14:341-345. Reprinted with permission.,CIO in Patients With Rheumatoid Arthritis,CS=corticosteroid; therapy = 7 mg prednisone equivalent per day. Density change measured as change in absolute or Z score (difference in standard deviation compared with healthy age-matched controls of the same race and sex) compared to baseline. Verhoeven AC, et al, 1997.,*P0.001; *P=0.002. Percentage of SLE patients (N=97) with low BMD, as measured by DXA. Kipen Y, et al, 1997.,CIO and Systemic Lupus Erythematosus,*,*,*,*,Potential Factors Causing Bone Loss in Inflammatory Bowel Disease,CorticosteroidsVitamin D / Calcium deficiencyPoor nutritional statusInflammationPhysical inactivityConcurrent medications (immunosuppressive agents),CIO and Chronic Obstructive Pulmonary Disease,*P0.05 vs. ISU or NSU; *P0.005 vs ISU. McEvoy CE, et al, 1998.,*,*,Pathophysiology of CIO: Overview,Bone remodeling occurs throughout adulthoodOsteoporosis results from an imbalance between osteoclast and osteoblast activityTwo metabolic abnormalities contribute to increased bone resorptionSecondary hyperparathyroidism due to decreased GI absorption and urinary excretion of calciumAltered gonadal function and decreased adrenal production of androgens,Pathophysiology of CIO,Calcium homeostasis Gonadal hormone Inhibit bone formation Increase bone resorption other,Calcium homeostasis,Decrease calcium and phosphate from GI tractsunknown mechanism Increase urinary calcium excretiondecrease calcium reabsorption at distal tubules Stimulatiom PTH secretion,Gonadal hormone effects,Decrease sex hormone : direct & indirectDecrease LH from pituitary gland : estrogen and testosteroneDecrease synthesis from adrenal glandsDecrease sex hormone binding globulin,Bone formation and bone resorption,Osteoblast- inh. Osteoblast proliferation - decrease matrix synthesis- increase apoptosis- decrease protein synthesis ( type 1 collagen and noncollagenous protein- decrease osteocalcin , IGF1, IGFBP3,5 , insulin-like growth factors, transforming growth factor B , prostaglandin E,Osteoclastincrease osteoclast activityincrease apoptosis of mature osteoclast,Bone formation and bone resorption,Osteoblast proliferationApoptosis OB numberProtein synthesis Bone formationDifferentiation Bone mass Fracture RiskAndrogenOsteoclast apoptosisBone resorptionOsteoclast formationPTHCalcium and phosphate absorption ( gut and kidney ),Glucocorticoid,Diagnosis of CIO: Initial Clinical Work-Up,Medical historyRisk factors for bone lossPhysical examClinical signs and symptoms,Patient Evaluation,History Documentation of height , weight , muscle strength , balance , vision Documentation of medical historyDocumentation of menstrual history, infertility in menFracture history and Family history of fracturesOther risk factors for osteoporosis : - Lifestyles influences : calcium and vitamin D intake, smoking, alcohol intake, medications, prevention of falling - Patient education : prevention of falling , exercise General health and prognosis,Patient Evaluation,Physical examinationEvidence of osteoporosis : evidence of fracture , kyphosis , loss of height , muscle strength and sizeGeneral physical findings : assessment of underlying disorder , other medical conditions,Patient Evaluation,Complete blood count and erythrocyte sedimentation rate ( ESR ) Serum calcium, phosphate, creatinine, electrolyte, alkaline phosphatase, 25-hydroxyvitamin D, estradiol, testosterone ( male ) 24 hr-Urinary calcium and creatinine BMD of spine and hip X-rays of appropriate areas,laboratory,Diagnostic Criteria*ClassificationT= 0 to -1 SD NormalT= -1 to -2.5 SDOsteopeniaT -2.5 SDOsteoporosisT -2.5 SD + fragility fracturesSevere osteoporosis* Measured in “T scores,” ie, the number of standard deviations below or above the peak bone mass in a young adult reference population of the same sex; SD=standard deviation.,WHO Criteria for Assessing Disease Severity,Guidelines for BMD Measurement,Baseline BMD prior to/within 6 months of initiating therapyAntero-posterior measurement of lumbar spine and femoral neckFollow-up at 6 and 12 months, annually thereafter until bone mass stabilizesMeasuring hip alone may miss more rapid loss in spine,Management of CIO: Goals of Treatment,Reduce fracture riskMaintain current BMD, prevent additional bone lossAlleviate pain associated with existing fracture(s)Maintain/increase muscle strengthInitiate lifestyle changes as needed,BMD, Vitamin D, and Calcium,Adachi JD, et al, 1996.,-12,-10,-8,-6,-4,-2,0,6,months,12,months,18,months,24,months,30,months,36,months,Change in lumbar spine BMD,from baseline (%),Vitamin D & calcium,Placebo,Pharmacologic Treatment of CIO: Overview,Pharmacologic treatment of CIO,Thiazide diuretics increase calcium absorption from GI tract decrease urinary calcium excretionFluorides stimulate osteoblast activityAnabolic steroids increase bone formation,Patient groupPostmenopausal women Premenopausal women w/intact ovarian functions (ages 13-50)Men,RecommendationEstrogen + progestin for women with intact uteriBisphosphonate or calcitonin if HRT contraindicated Estrogen-containing OCs (50 g estradiol) or equivalentBisphosphonate or calcitonin ifestrogen contraindicatedTestosterone (if serum testosterone levels low)Bisphosphonate or calcitonin if testosterone contraindicated,Hormone Replacement Therapy in the Treatment of CIO: ACR Guidelines,American College of RheumatologyTask Force on Osteoporosis Guidelines, 1996.,-0.06,-0.04,-0.02,0,0.02,0.04,0.06,Group 1,Prednisone,only,Group 2,Prednisone,+ ERT,Group 3,Control,Group 4,ERT only,Changes in lumbar spine BMD (g/cm,2,),at 1 year,Estrogen Replacement Therapy in the Treatment of CIO,*P=0.008 vs. baseline; P=0.027 between groups 1 and 2. Lukert BP, et al, 1992.,*,Testosterone Replacement Therapy in the Treatment of CIO,*P=0.005 vs control; P=0.05 between-group difference. Reid IR, et al, 1996.,*,-5.0,-2.5,0.0,2.5,5.0,Testosterone therapy,period,Control period,Changes in lumbar spine BMD (%),at 1 year,Cyclical Etidronate and Prevention of Corticosteroid-Induced Bone Loss,*P0.05 between-group difference. Adachi JD, et al, 1997. Roux C, et al,1998.,*,*,-4,-3,-2,-1,0,1,2,Lumbar,spine,Femoral,neck,Trochanter,Lumbar,spine,Femoral,neck,Trochanter,Changes in BMD from baseline (%) at 1 year,Etidronate,Control,0,2,4,6,Lumbar spine*,Femoral neck,Trochanter,Change in BMD from baseline (%),Men,Pre-menopausal women,Post-menopausal women,Etidronate: Pooled Results from Three Randomized Trials,*P0.05 between-group difference. Roux C, et al,1998.,Efficacy of Pamidronate in the Prevention of Bone Loss,Boutsen Y, et al, 1997.,-6,-4,-2,0,2,4,6,6 months,12 months,6 months,12 months,Changes in BMD from baseline (%),Pamidronate + calcium,Calcium only,Efficacy of Alendronate in Increasing BMD,*P 0.001 vs. control; *P 0.01 vs. control; P 0.001 vs. baseline, P 0.01 vs. baseline; Saag KG, et al, 1998.,*,*,*,*,*,*,*,Efficacy of Alendronate: Two Years Follow-Up,*P0.001 vs. control; *P0.01 vs. control; P0.05 vs. control. Saag KG, et al, 1998.,*,*,*,*,-4,-3,-2,-1,0,1,2,3,4,Lumbar spine,Femoral neck,Trochanter,Change in BMD from baseline (%),Control,Alendronate 10 mg,Alendronate 5 mg,Alendronate 2.5 mg year 1, 10 mg year 2,Effect of Risedronate on BMD inPatients Initiating Corticosteroid Therapy,*P0.05 vs control. Cohen S, et al, 1998.,*,*,*,*,*,*,-4.0,-2.0,0.0,2.0,4.0,Lumbar spine,Femoral neck,Trochanter,Change in BMD from baseline (%),at 12 months,Control,Risedronate 2.5 mg,Risedronate 5 mg,Effect of Risedronate on BMD in Patients on Long-Term Corticosteroid Therapy,*P0.05 vs. control. Devogelaer JP, et al, 1998.,*,*,*,*,-3.0,-2.0,-1.0,0.0,1.0,2.0,3.0,Lumbar spine,Femoral neck,Trochanter,Change in BMD from baseline (%),at 12 months,Control,Risedronate 2.5 mg,Risedronate 5 mg,0,5,10,15,20,Pooled control patients,Pooled risedronate,patients,Patients with vertebral fractures (%),Effect of Risedronate on Vertebral Fracture Rates,Pooled vertebral fracture rates from 518 patients on steroid therapy. *P=0.016 vs. control. Reid D, et al, 1998.,*,TreatmentNumber of Change in lumbar pooled trials spine BMD (%)* Vitamin D18+1.96 Calcitonin11+2.11 Bisphosphonates18+5.31,Bisphosphonates in the Management of CIO: A Meta-Analysis,*Compared with no treatment or with calcium aloneP=0.0001 compared with calcitonin or vitamin D,Glucocorticoid therapy evaluation,Plan- at start of glucocorticoid therapy1. Minimize glucocorticoid dose 2. Use alternate day therapy , topical steroid or bone sparing steroid if possible 3. Prescribe exercise ( weight baring ) , physical therapy , prevent falling 4. Avoid smoking and excess alcohol5. Assure adequate calcium intake 6. Add supplement calcium up to 1000-15000 mg calcium /day7. Add multivitamin containing 400-800 IU vitamin D 8. BMD measurement of the spine and hip : if T-score lower than 1 SD start HRT and if more than 1 SD start HRT only in postmenopausal woman,Glucocorticoid therapy evaluation,Reassessment at 2-3 mo1. Review glucocorticoid therapy : attempt to decrease or discontinue2. Assess exercise and calcium intake3. Measure serum calcium , 24 hr urinary calcium if more than 4 mg/kg/d use hydrochlorothiazide 25-50 mg twice daily Reassessment at 6 mo 1. Review glucocorticoid therapy and minimize 2. Assess exercise and calcium intake 3. Repeat serum calcium and 24 hr urinary calcium measurement4. Alter calcium / vitamin D / thiazide therapy if necessary 5. If pateint is to continue glucocorticoid ,consider to repeat BMD 6. Consider HRT / bisphosphonate/ calcitonin,Glucocorticoid therapy evaluation,Reassessment at 1 yr 1. Review glucocorticoid therapy and minimize2. Assess exercise and calcium intake 3. Repeat serum calcium and 24 hr urinary calcium measurement4. BMD measurement ( spine and hip ) 5. Alter calcium / vitamin D / thiazide therapy if necessary6. Alter further thereapy if bone loss if continuesReassessment thereafter if glucocorticoids continue1. Repeat annual assessment as above 2. Change therapy as needed3. Consider newer drugs as they become available,ACR Task Force on Osteoporosis: Initiating Long-Term Corticosteroid Therapy,Initial history & physical, lab/DXA measurementsCalcium/vitamin D supplementationPatient education,T score -1Monitor regularly,One month follow-up:Obtain 24h urine to measure calciumIf 300 mg/d: add thiazide diureticAdjust dosage of calcium and vitamin D supplementation,6-12 months follow-up:Repeat BMDDecrease 5%: change/add medicationIncrease, no change, or decrease 5 % young adults or Lower than 1 SD below the Screen for hypogonadism bone loss mean for aged-match controls NoIf hypogonadism present : Calcium 1000 mg/dayAdd hormone replacement with Vitamin D 400-800 IU/day Estrogen