Presentation on theme: "Osteoporosis Diagnosis and Therapy"— Presentation transcript:
1 Osteoporosis Diagnosis and Therapy Veronica Piziak MD, PhDScott & WhiteProfessor of EndocrinologyTexas A&M HSC
2 Objectives Disclosures: Warner Chilcott- speaker Discuss: Diagnosis of osteoporosisDosages of calcium and vitamin D and their role in bone diseaseRisks and benefits of bisphosphonatesRole of DenosumabDisclosures: Warner Chilcott- speakerNovartis, P+G research support
3 Bone loss accelerates with menopause (~1%-2% per year) HIGHER PEAKBONE MASSMANOPAUSEBone loss accelerates withmenopause (~1%-2% per year)Age-related bone loss(~0.5%-1.0% per year)AGE in YEARS
4 How much calcium? What kind? Patients with renal insufficiency may not be able to clear usual doses of calcium and coronary artery calcification may progressRusso D, Miranda I, Ruocco C, Battaglia Y, Buonanno E, Manzi S,et al. The progression of coronary artery calcification in predialysis patients on calcium carbonate. Kidney Int 2007;72:
5 X700 mg1200 mg1000 mg1300 mgInstitute of Medicine 2010
6 Calcium: How much and what kind? Do calcium supplements increase the risk of heart attack?Meta analysis:Medline, Embase, and Cochrane CentralRegister of Controlled Trials (1966-March 2010),1-2 gms calcium no D in supplementsHazard ratio 1.31 pDietary calcium no increased risk MIBoland et al BMJ 2010; 341:c3691
7 Calcium intake and vascular calcification No correlation of coronary artery calcification or abdominal aortic calculations with dietary calcium or calcium intake in healthy men and women.Wang TK et al JBMR Jul 2010Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5‐year RCT and a 4.5‐year follow‐upNo increased incidence of CV disease mg/dayJoshua R Lewis JBMR on line 2010Look at the ASBMR website
11 HISTORY OF RENAL STONES 1000 mg calcium citrateMeasure urine calciumIf > 3.5mg/kg/dayUse HCTZ 12.5mg/dayEncourage hydrationDietary calciumInversely related to the risk of renal stones in >8000 womenCURHAN ANN INT MED;97:
12 DOES CALCIUM PREVENT FRACTURES? Review of 14 trialsCalcium + D vs control7 trials studied hip fracture7 trials studied nonvertebralCalcium reduces fracturesCalcium + D (400 IU)No better than calcium aloneGillespie AA et al Cochrane Database System Rev 2005
17 THE 25(OH)D CONTINUUM “deficiency” “insufficiency” “normal” 10 20 30 ?102030405060(ng/ml)(ng/mL)255075100125150(nmol/L)PTH is elevatedmodified after HeaneyCALCIUM ABSORPTION INCREASES
18 Who to Screen for Deficiency Patients who do not increase BMD on bisphosphonatesPatients with hip fracture, nonunion fracturesYoung patients with fracture at any sitePatients with hyperparathyroidism
19 Who to Screen for Deficiency Breast fed infants not given vitamin D supplementationInstitutionalized elderly- decreased sunshine exposureObese individuals – decreased productionFibromyalgia patients ?Paget’s disease – Rapid bone turnoverMedications that interfere with vitamin D absorption or metabolism.
20 Who to Screen for Deficiency MalabsorptionPancreatic insufficiencyInflammatory bowel diseaseGastric bypassSevere Liver dysfunction -decreased 25 hydroxylation
21 Replacing Vitamin D 1000 IU daily from the 25-30 range Raises the level to about 40 ng/mlFor significant deficiency50,000 IU (D2) may give once a week for 8 weeks check 25OH DHolick et al 1998 lancet 351:805May give 50,000 IU once a month safely for 5 years
22 VITAMIN D AND FRACTURES Meta analysis7 trials womenMean age 79Vitamin D doses IU were necessary to reduce fracture 25%Calcium intake variableBaseline vitamin D unknownBISCHOFF-FERRARI ET AL JAMA 2005;293:
23 Definition of Osteoporosis A skeletal disorder characterized by…Excessive osteoclast-mediated bone resorptionCompromised bone strengthIncreased risk of fracture at all skeletal sitesNormalOsteoporosisAccording to the NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. In addition to the physical effects, osteoporosis has financial and psychosocial consequences, all of which significantly affect the individual, the family, and the community.1The images show micro-computed tomography (microCT) scans of normal and osteoporotic paired iliac crest bone biopsies in a patient at 53 and then 58 years old. Note, the thinning and perforations of both the cortical and trabecular bone.1. NIH Consensus Development Panel. JAMA. 2001;285:“Osteoporosis has financial, physical, and psychosocial consequences,all of which significantly affect the individual, the family,and the community.” –NIH Consensus StatementBoyle WJ, et al. Nature. 2003;423:NIH Consensus Development Panel. JAMA. 2001;285:Images are of a paired iliac crest biopsy and courtesy of Yebin Jiang MD, PhD. Osteoporosis & Arthritis Lab, University of Michigan.
24 WHO Diagnostic Categories for Osteopenia T-ScoreOsteopeniaOsteoporosisNormal–2.5–2–1WHO. Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis; 1998.Guidelines established by the World Health Organization (WHO) in 1998 designated 4 diagnostic categories for osteoporosis in postmenopausal Caucasian women1:Normal: BMD representing a T-score ≥ –1.0Osteopenia: BMD representing a T-score between –1.0 and –2.5Osteoporosis: BMD representing a T-score < –2.5Severe (established) osteoporosis: BMD representing a T-score < –2.5 and the presence of 1 or more fragility fracturesIn studies of populations, the lower the T-score, the higher the risk for fracture.These categories were established on the basis of data available at the time.The critical clinical question is, When should a physician intervene and begin treatment?Reference1. World Health Organization. Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis. Geneva, Switzerland: WHO; 1998:5-6.REMEMBER BONE STRENGTH ,DISEASE STATEWHO = World Health Organization.
25 BMD TestingRecommended by the Surgeon General’s report in 2004: US Preventive health task force 3/2011Postmenopausal women with FRAX score 9.3% risk osteoporotic fractureWomen>/=65 years of age with fractures - required by NCQAYounger women with risk factorsMen and Women with fragility fracturesPeople on medications or with diseases that can increase the risk of fractures
26 Who to treat? Goal - prevent fractures Patients at significant risk
27 No. of Women With Fractures Population BMD Distribution, Fracture Rates, and Number of Women With FracturesFracture rate605040302010Fracture per 1000 Person-YearsNo. of women with fractures45035030025020010015050400No. of Women With FracturesBMD distributionThe concept of fracture risk being a continuum is well demonstrated by looking at the frequency distribution of BMD T-scores in the population of women studied in NORA.The BMD T-score distribution displays a normal (Gaussian) distribution.If the WHO diagnostic categories for osteoporosis are considered as a diagnostic and fracture threshold, then this would imply that the majority of fractures would occur below a T-score of –2.5.This slide, drawn from the NORA study, shows the increasing incidence of fracture risk as a function of declining BMD status. (Note that these BMD measurements were made with peripheral rather than central dual-energy x-ray absorptiometry [DXA].)1Approximately half of the fractures occur above a T-score of –2.5. Therefore, to prevent fractures, clinical consideration must be given as well to patients with T-scores above –2.5.1Again, the concept here is that fracture risk is a continuum, not an absolute threshold.Reference1. Siris ES, Chen Y-T, Abbott TA, et al. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med. 2004;164:BMD T-Scores (Peripheral)>1.01.0 to 0.50.5 to 0.00.0 to –0.5–0.5 to –1.0–1.0 to –1.5–1.5 to –2.0–2.0 to –2.5–2.5 to –3.0–3.0 to –3.5< –3.5Adapted from Siris ES, et al. Arch Intern Med. 2004;164:
30 Problems with FRAXUnder estimates fracture risk in healthy women under 56 – Use hip BMDExcellent for women 60 plusNot accurate if patient has been on bone active agentsTremollieres FA et al JBMR 25:
31 Updated NOF Clinician’s Guide Incorporation of WHO Algorithm Previous NOF Guide (2003)Initiate Treatment in those with :T-score <-2.0 & no risk factorsT-score <-1.5 & ≥ risk factorsHip or Vertebral FractureNew NOF Guide (2008)Initiate Treatment in PM women and men age ≥50 with:Hip or vertebral fractureOther prior fracture and low bone mass (T-score -1.0 to -2.5)T-score <-2.5 (2º causes excl.)Low bone mass and 2º causes associated with high risk of fractureLow bone mass AND 10-yr hip fracture probability ≥3% or 10-yr major OP-related fracture probability of ≥20%
32 OSTEOPOROSIS How to Treat? Approved medicationsRaloxifeneBisphosphonatesPTH 1-34Denosumab
33 ALENDRONATE Approved for: Prevention and therapy Postmenopausal osteoporosisSteroid induced osteoporosis70mg/weekGeneric available!Long life in bone, most commonly associated with bone suppression
34 Risedronate and Ibandronate Risedronate 150 mg Once a MonthMinimum of 30-minute wait before eatingApproved for prevention and therapy ofPostmenopausal osteoporosis, male osteoporosis, steroid induced osteoporosisEnteric coated form now availableKey Points:Additional less frequent dosing options are in development with 150 mg Once a MonthIbandronate 150 mg Once a MonthMinimum of 60 minute wait before eatingApproved for prevention of vertebral fractures
35 IV Bisphosphonates: Considerations Potentially increased complianceOnly eliminate GI adverse eventsAdverse events and considerationsFlu-like syndromesInjection-site reactionsRenal toxicities (Check creatinine)Long-term useOsteonecrosis of the jawElectrolyte abnormalities (hypocalcemia)Issues concerning the use of intravenous bisphosphonatesIntravenous bisphosphonate administration usually occurs in a clinical setting, which significantly increases compliance.Adverse events associated with IV bisphosphonates:Flu-like syndromesInjection site reactionsRenal toxicities (zoledronic acid)Adverse events associated with long-term use of bisphosphonates are osteonecrosis of the jaw and electrolyte abnormalities (hypocalcemia).Conte et al. Oncologist. 2004;9(suppl 4):28.Conte P, Guarneri V. Safety of intravenous and oral bisphosphonates and compliance with dosing regimens. Oncologist. 2004;9(suppl 4):28-37.
36 IV Ibandronate 15 second IV push Store at room temperature 3 mg/every three monthsCreatinine clearance at least 37 ml/min
37 Zoledronic acid/ Reclast Approved as a once / year IV therapy for postmenopausal and male osteoporosis,15 minute infusion 5 mg/100 mlSide effects – hypocalcemia, fever, muscle pain, flu-like symptoms and headacheNot for use in pregnancy or with creatinine clearance < 35ml/minMAKE SURE PATIENTS TAKE CALCIUM!MAKE SURE THEY ARE WELL HYDRATEDConsider obtaining 25 OH Vitamin D
38 Code properly Billed under Medicare Part B Must have “senile/postmenopausal osteoporosis T- score -2.5+Unspecified adverse effect of other drugV12.79 Personal Hx of digestive system diseaseV49.84 bed confined status= payment
39 Hip fracture reduction by 9 months RISEDRONATE CONTROLHip fracture reduction by 9 monthsP < 0.01VS CONTROL
40 ALENDRONATE OVER 10 YEARS BONE AND LIBERMAN ET AL NEJM 2004;350:1189-1199
41 FLEX – FIT EXTENSIONSAFE FOR 10 YEARSNO ONJOVERSUPRESSION OF BONE WAS NOT SEENWHAT HAPPENS WHEN YOU STOP ALENDRONATE AFTER 5 YEARS?NO EXCESS IN ALL CLINICAL FRACTURES IN THE UNTREATED GROUPTHERE WAS A 2.9% INCREASE IN CLINICALLY DETECTED VERTEBRAL FRACTURES.
42 BUT does over suppression result in fractures? In the past 4 years, reports have been published implying that long-term bisphosphonate therapy could be linked to atraumatic femoral diaphyseal fracturesLong-term alendronate therapy 8+ years ? Associated with unilateral low-energy subtrochanteric and diaphyseal femoral fractures in a small number of patients.
43 JBMR Publishes ASBMR Task Force Report on Atypical Femoral Fractures Who is at risk? Date: September 14, 2010In the most comprehensive scientific report to date on the topic, the task force reviewed 310 cases of "atypical femur fractures," and found that 94 percent (291) of patients had taken the drugs, most for more than five years. The task force members emphasized that atypical femur fractures represent less than one percent of hip and thigh fractures overall and therefore are very uncommon. They MAY be related to long term use.More than half of patients with atypical femur fractures reported groin or thigh pain for a period of weeks or months before fractures occurred, according to the report. More than a quarter of patients who experienced atypical femur fractures in one leg experienced a fracture in the other leg as wellWarnings PI: Thigh or groin pain look for fracture –Plan film of the area may show sclerosis.
44 FLEX – FIT EXTENSION WHO SHOULD NOT STOP? PREVIOUS VERTEBRAL OR NONVETEBRAL FRACTUREVERY LOW BMD <- 2.5BLACK ET AL JAMA 2006;296:EDITORIAL JAMA 2006;296:FDA agrees 2010
45 FDA opinion 3/10/10FDA reviewed Abrahamsen et al, that analyzed data from two large observational studies in patients with osteoporosis.The authors concluded that atypical subtrochanteric femur fractures had many similar features in common with classical osteoporotic hip fractures, including patient age, gender, and trauma mechanism.The data showed that patients taking bisphosphonates and those not taking bisphosphonates had similar numbers of atypical subtrochanteric femur fractures relative to classical osteoporotic hip fractures. More adherence fewer fracturesJ Bone Miner Res. 2009;24:
46 Reanalysis of FLEX/FIT who could stop? In previous studies, ALN efficacy for NVF prevention in women without prevalent vertebral fracture was limited to those with femoral neck (FN) T-score </= -2.5.Continuing alendronate for 10 years instead of stopping after 5 years reduces non-vertebral fracture risk in women without prevalent vertebral fracture whose FN T-score, achieved after 5 years of ALN, is </= -2.5, but does not reduce risk of NVF in women whoseT-score is > -2 after 5 years could stop
47 Long Term Use– a Plan Drug holiday after 5-10 years Duration of the treatment and holiday depend on fracture risk.Continue for 10 years if osteoporosis or if holiday use another agent (? PTH 1-34)Low fracture risk then stop at 5 years and monitor the DXA stay off if stable and no fractures.Watts et al JCE&M 95:
48 Bisphosphonates and esophageal cancer Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohortData from patients using medications for three or more years. Risk of esophageal cancer doubled in users. 1/1000 to 2/1000.Looked at age, sex, smoking, alcohol intake, or body mass index; by diagnosis of osteoporosis, fracture, or upper gastrointestinal disease; or by prescription of acid suppressants, non-steroidal anti-inflammatory drugs, and corticosteroids.Don’t use orals in high risk patientsBMJ Sep 1;341:c4444
49 Human Parathyroid Hormone 1-34 and 1-84110H2N-SerValGluIleGlnLeuMetHisAsnGlyLysArgTrpAspPhe203040Parathyroid hormone (PTH) is secreted by the parathyroid glands and is an important regulator of blood calcium concentrations. Synthesis and secretion of PTH are stimulated by a decrease in blood calcium. PTH has three actions: 1) Increase the release of calcium from bone, 2) Reduce renal clearance of calcium, and 3) Stimulate the production of 1,25 (OH)2D3.. Human parathyroid hormone is a single chain polypeptide with 84 amino acids and a molecular weight of 9425 Da. The N-terminal region, 1-34, shown here in yellow, is biologically active and sufficient for regulation of mineral ion homeostasis.50706080-COOH
50 When to use Severe osteoporosis T score – 3, previous fractures Fractures on bisphosphonateUnresponsive to bisphosphonatesFew side effectsVery expensive
51 PTH 1-34 2 YEARS FOLLOWED BY BISPHOSPHONATE IN MEN Kurland ES et al. Osteoporos Int. 2004;15:
53 RANKL-Inhibitors: Mechanism of Action OPGRANKLRANKInhibitorsCFU-MCytokines Growth factors HormonesRANKLOPGPrefusionosteoclastMultinucleatedosteoclastDenosumab, a RANKL inhibitor, blocks the binding of RANKL to RANK, resulting in the inhibition of osteoclast formation, function, and survival.Denosumab is a RANKL inhibitor that blocks the binding of RANKL to RANK and mimics the activities of the endogenous OPG (RANKL inhibitor).1Blocking the activation of RANK results in the inhibition of osteoclast formation, function, and survival.2By inhibiting osteoclast activity, bone loss is reduced.2Active OsteoclastOsteoblastStromal cellsBONEAdapted from Boyle et al. Nature. 2003;423:337.1. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:2. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:
54 Denosumab SC q6mo: Effect on Lumbar Spine BMD -2-1123456Placebo (n=46)from baseline (%)Mean changeDenosumab 14 mg (n=53)Denosumab 60 mg (n=46)Denosumab 100 mg (n=41)Denosumab 210 mg (n=46)Alendronate70 mg/wk (n=46)Denosumab significantly increased lumbar spine BMD at 12 months; thus the primary end point of this study was achieved.The primary end point of this study was the mean percentage change from baseline in lumbar spine BMD at 12 months.The mean increase in lumbar spine BMD was 3.0% to 6.7% at 12 months across all denosumab dose groups (including the every-3-month doses), as compared with a 0.8% decrease for placebo (P<0.001).Significant changes in lumbar spine BMD were evident as early as 1 month in patients receiving 14 and 30 mg every 3 months and 60 mg every 6 months, compared with a 0.6% decrease with placebo (P<0.05).At 12 months, alendronate significantly increased BMD as compared with placebo. In exploratory comparisons, the mean change in lumbar spine BMD for alendronate (4.6%) was similar to denosumab.2468101260 mg dose sub q every 6 monthsSpine 6.5% 2 years, Hip 3.4%, Radius 1.4% (cortical bone)96% responder rate 4/1/08 Endo SocMonthsAdapted from McClung et al. N Engl J Med. 2006;354:821.McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:
55 Steven R. Cummings, M. D. , Javier San Martin, M. D. , Michael R Steven R. Cummings, M.D., Javier San Martin, M.D., Michael R. McClung, M.D., NEJM 2009;361 Aug 19th
56 Approved by the FDA! Denosumab (Prolia) Indication: postmenopausal osteoporosisWith a high risk of fractureSub q every 6 months (prefilled syringe)Contraindicated in hypocalcemiaMay use in renal insufficiency ( monitor calcium, phosphorus, magnesium)
57 Side EffectsSide effects: dermatitis, significant infections, pancreatitisONJ has been reportedExamine the mouthIf patient has an infection they need to call
58 TREAT OSTEOPOROSIS10 million Americans with osteoporosis and it is treatableYetCalcium intake is low in the USAfter hip fracture<25% given calcium and vitamin d<10% treated with bone active agents50% no longer take medications at 1 yearKeep trying