Presentation on theme: "Update on Management of Osteoporosis"— Presentation transcript:
1 Update on Management of Osteoporosis E. Michael Lewiecki, MDNew Mexico Clinical Research & Osteoporosis CenterUniversity of New Mexico School of MedicineAlbuquerque, NM
2 Faculty DisclosureIt is the policy of the American Society for Bone and Mineral Research (ASBMR) and The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a faculty member with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The American Society for Bone and Mineral Research (ASBMR) and The France Foundation have identified and resolved any and all faculty conflicts of interest prior to the release of this activity.
3 Disclosure Grant / Research Support Amgen, Eli Lilly, Merck, Novartis, Warner ChilcottConsultant, Advisory Board, Speakers’ Bureau, or Sponsored Speaking Events
4 Learning ObjectivesImprove the ability to assess risk factors for osteoporosis and apply evidence-based screening recommendations to these at-risk patients within one’s practiceDevelop strategies to improve the treatment of patients with osteoporosisUtilize the tools and other information provided within this initiative, including patient education tools and systems- based approaches to facilitate improving the assessment and care being provided to patients with osteoporosis
5 Postmenopausal Osteoporosis in the Primary Care Setting What is osteoporosis?Why you should care?Whom to test and how?Whom to treat and how?
6 Definition of Osteoporosis A skeletal disorder characterized byCompromised bone strength predisposing toAn increased risk of fractureBone strength reflects the integration of two main features:Bone densityBone qualityNormal BoneThe “old” definition distinguished osteoporosis (in which the makeup of bone was normal) from osteomalacia (in which mineralization was clearly abnormal).The “modern” definition introduces the importance of bone quality (micro-architecture). Although this definition dates back to 1991, there is still no clinical test of bone quality. Thus, the clinically-relevant parts of the definition are bone mass and fractures.Osteoporotic Bone2000 NIH Consensus Development Conference
7 Osteoporosis Is a Serious Public Health Problem At age 50, lifetime risk of fracture is1:2 women1:5 menAffects 10 million Americans8 million women2 million menAdditional 34 million have low bone mass2 million fractures yearly*Direct cost $17 billion*Distribution of Fractures*Based on figures from Cost does not include lost productivity, unpaid caregiver time, transportation and social servicesNOF Fast Facts. Accessed February 2013.Burge R, et al. J Bone Miner Res. 2007;22:USDHHS. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD
8 Identified Treatment Gap NCQA HEDIS HEDIS Measure% Compliance*Beta-blocker persistence after a heart attack81.3%Breast cancer screening70.5%Colorectal cancer screening62.4%Osteoporosis management after a fracture22.8%*2011 HMO RatesNCQA State of Healthcare HMO Statistics (Commercial or Medicare data from 2011).Accessed February 2013.
9 National Osteoporosis Foundation 2013 Guidelines Major clinical recommendationsUniversal (risk, diet, vitamin D, exercise, smoking, monitoring)Diagnosis (BMD, vertebral imaging, causes of secondary osteoporosis)Monitoring (BMD)Treatment (initiation criteria, options, duration)Accessed March 2013.
10 Who Should Have a Bone Density Test? AAFP1 and NOF2Women age 65 and older and men age 70 and olderYounger postmenopausal women and men ages –69 with clinical risk factorsAdults who have a fracture after age 50Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids) associated with low bone mass or bone lossConditions, Diseases and Medications That Cause or Contribute to Osteoporosis and FracturesLifestyle factorsAlcohol Abuse High salt intake FallingLow calcium intake Inadequate physical activity Excessive thinnessVitamin D insufficiency ImmobilizationExcess vitamin A Smoking (active or passive)Genetic factorsCystic fibrosis Homocystinuria Osteogenesis imperfectaEhlers-Danlos Hypophosphatasia Parental history of hip fractureGaucher’s disease Idiopathic hypercalciuria PorphyriaGlycogen storage diseases Marfan syndrome Riley-Day syndromeHemochromatosis Menkes steely hair syndromeHypogonadal statesAndrogen insensitivity Hyperprolactinemia Premature ovarian failureAnorexia nervosa and bulimia Premature menopause Athletic amenorrheaTurner’s & Klinefelter’s syndromes PanhypopituitarismEndocrine disordersAdrenal insufficiency Cushing’s syndrome Central AdiposityDiabetes mellitus (Types 1 & 2) Hyperparathyroidism ThyrotoxicosisGastrointestinal disordersCeliac disease Inflammatory bowel disease Primary biliary cirrhosisGastric bypass MalabsorptionGI surgery Pancreatic diseaseHematologic disordersMultiple myeloma Monoclonal gammopathies Sickle cell diseaseHemophilia Leukemia and lymphomas Systemic mastocytosisThalassemiaRheumatologic and autoimmune diseasesAnkylosing spondylitis Lupus Rheumatoid arthritisOther rheumatic and autoimmune diseasesCentral nervous system disordersEpilepsy Parkinson’s disease StrokeMultiple sclerosis Spinal cord injuryMiscellaneous conditions and diseasesAIDS/HIV Congestive heart failure Muscular dystrophyAlcoholism Depression Post-transplant bone diseaseAmyloidosis End stage renal disease SarcoidosisChronic metabolic acidosis Hypercalciuria Weight lossChronic obstructive lung disease Idiopathic scoliosisMedicationsAluminum (in antacids) Cyclosporine A and tacrolimus Proton pump inhibitorsAnticoagulants (heparin) Depo-medroxyprogesterone (premenopausal contraception) Selective serotonin reuptake inhibitorsAnticonvulsants Glucocorticoids (≥ 5 mg/d prednisone or equivalent for ≥ 3 months) Tamoxifen® (premenopausal use)Aromatase inhibitors GnRH (Gonadotropin releasing hormone) antagonists and agonists Thiazolidinediones (such as Actos® and Avandia®)Barbiturates Lithium Thyroid hormones (in excess)Cancer chemotherapeutic drugs Methotrexate Parenteral nutrition1. Sweet MG, et al. Am Fam Physician. 2009;79(3):2. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Accessed February 2013.
11 Reimbursement for DXA Final Rule Since 2006, Medicare covers bone densitometry for five indicationsEstrogen-deficient women at clinical risk for osteoporosisPatients with vertebral abnormalitiesPatients receiving long-term glucocorticoids (prednisone ≥ 5 mg/d or equivalent for 3+ months)Patients with primary hyperparathyroidismPatients being monitored to assess the response to an approved drugFederal Register. 2006;71(231):
12 WHO Criteria for Postmenopausal Osteoporosis The T-score compares an individual’s BMD with themean value for young adults and expressesthe difference as a standard deviation score.Kanis JA, et al. J Bone Miner Res. 1994;9:-2.5 and belowOsteoporosisBetween -1.0 to -2.5Low bone mass (osteopenia)-1.0 and aboveNormalT-scoreCategory
13 NOF Treatment Guidelines 2013 Women ≥ 65 and men ≥ 70(younger with risk factors)DXAT-score between -1.0 and -2.5and high fracture riskT-score ≤ -2.5 in the lumbar spine, total hip, or femoral neckorHip or spine (clinical or radiographic) fracture≥ 3% for hip fractureor≥ 20% for major osteoporotic fractureFRAX10-y fracture riskCandidate for TREATMENTYESAccessed March 2013.
20 Clinical Benefits of FRAX Derives 10-year probability of clinical event from measurable parametersInternationally recognized and validatedBased on data from multiple cohortsEasily accessible on the Internet or DXA softwareHelps identify patients who need treatmentCurr Osteoporos Rep December; 8(4): 192–197.The Utility and Limitations of FRAX: A US PerspectiveStuart L. Silverman and Andrew D. CalderonAbstractThe FRAX calculator is a major achievement in terms of our understanding of measuring fracture risk. Along with being an easily accessible web-based tool, it is the only model based on extensive data on multiple cohorts. FRAX will help clinicians identify individuals who need osteoporosis treatments, while also screening out those who do not require osteoporosis treatments. However, FRAX is limited by a number of factors. Although it is web based, few physicians have the means to access it. It also assumes that body mass index and mortality are constant across different racial and ethnic groups. FRAX is further limited by the exclusion of variables known to be associated with fracture risk, lack of dose-response relationships for variables, increased subsequent fracture risk after initial fracture, restriction to only one bone mineral density site, racial and ethnic differences that may influence fracture risk, and availability of racial and ethnic fracture risk data to be used in the FRAX calculator. Finally, the values obtained from FRAX should not take the place of good clinical judgment.
21 Limitations of FRAX™ WHO Fracture Probability Tool Not valid in patients on treatmentOnly hip BMD is consideredRisk is “yes/no” – there is no consideration of “dose” (e.g., fractures, glucocorticoids, smoking, alcohol)Not all risk factors are included (e.g., falls)“Major osteoporotic fracture” is not the same as all osteoporotic fracturesClinical judgment is requiredWatts NB, et al. J Bone Miner Res 2009;24:
22 Patient Care Goals Identify patients at risk of fractures Reduce incidence of fracturesMaintain quality of lifeActivityIndependenceHealth
23 Universal Recommendations Counsel on the risk of fracturesCalcium intake as follows, ideally through diet, with supplements if necessary1000 mg per day for men 50-701200 mg per day for women ≥ 511200 mg per day for men ≥ 71Vitamin D intake should be 800-1,000 IU per day, supplemented if necessary (age ≥50)Regular weight-bearing and muscle-strengthening exerciseFall prevention evaluation and trainingAs highlighted by the recent US Preventive Services Task Force recommendations (http://www.uspreventiveservicestaskforce.org/uspstf/uspsvitd.htm) vitamin D and calcium remain controversial. The NOF guidelines extracted for this slide describe vitamin D insufficiency [serum 25-hydroxyvitamin D (25(OH)D) < 30 ng/ml (75 nmol/L)] as a risk factor for falls and adds that “Patients with recent fractures, multiple fractures or very low BMD should be evaluated for secondary etiologies and, when considering osteomalacia or vitamin D insufficiency, a serum 25(OH)D level should be obtained.” Thus clinical judgment should dictate whether supplementation alone or with serum monitoring is appropriate for each patient.The 2010 AACE guidelines (Watts et al are explicit about monitoring vitamin D: “Maintain adequate vitamin D intake; supplement vitamin D, if needed, to maintain serum levels of 25-hydroxyvitamin D [25(OH)D] between 30 and 60 ng/mL (Grade A; BEL 1).”Accessed March 2013.
24 FDA-approved Medications Indications Postmenopausal OsteoporosisGlucocorticoid-induced OsteoporosisMenDrugPreventionTreatmentEstrogenCalcitonin*(Miacalcin®, Fortical®)Raloxifene (Evista®)Ibandronate (Boniva®)Alendronate (Fosamax®)Risedronate (Actonel®)Risedronate (Atelvia®)Zoledronate (Reclast®)Denosumab (Prolia™)Teriparatide (Forteo®)Paget’s dose: alendronate 40 mg/day x 6 mo., risedronate 30 mg/day x 2 mo.*FDA advisory board found that evidence did not support calcitonin salmon for thetreatment of osteoporosis (March 5, 2013)
25 Evidence for Fracture Reduction DrugVertebral FractureNonvertebral FractureHipFractureCalcitonin(Miacalcin®, Fortical®)No effect demonstratedRaloxifene (Evista®)Ibandronate (Boniva®)Alendronate (Fosamax®)Risedronate (Actonel®, Atelvia®)Zoledronic acid (Reclast®)Denosumab (Prolia™)Teriparatide (Forteo®)Adapted from Murad MH, et al. J Clin Endocrinol Metab. 2012;97(6):
26 Bisphosphonates Side Effects/Safety Concerns May cause esophageal irritation (oral)Can cause acute phase response (IV and high-dose oral)Contraindicated in patients with hypocalcemiaLimited to patients with good kidney function (GFR > 30 or 35 mL/min)Musculoskeletal pain?Osteonecrosis of the jaw?Atypical femur fractures?
27 Bisphosphonates “Side Benefits” Decreased risk of breast cancer1-5Decreased risk of colorectal cancer6Decreased risk of stroke7Reduced risk of gastric cancer8Decreased overall mortality9,101. Chlebowski RT, et al. J Clin Oncol. 2010;28:2. Dreyfuss JH. CA Cancer J Clin. 2010;60:3. Newcomb PA, et al. Br J Cancer. 2010;102:4. Rennert G, et al. J Clin Oncol. 2010;28:5. Vestergaard P, et al. Calcif Tissue Int. 2011;88:6. Rennert G, et al. J Clin Oncol. 2011;9:7. Kang JH, et al. Osteoporos Int. 2012;23(10):8. Abrahamsen B, et al. J Bone Miner Res. 2012;27:9. Center JR, et al. J Clin Endocrinol Metab. 2011;96:10. Sambrook PN, et al. Osteoporos Int. 2011;22:
28 Bisphosphonates How Long Should Treatment Last? Bisphosphonates have a long residence time in boneWhen long-term therapy is stopped, is sufficient drug available to exert a continuing benefit?Does long-term treatment create safety concerns that limit the duration of treatment?Long-term use of bisphosphonates in osteoporosis.J Clin Endocrinol Metab Apr;95(4): Watts NB, Diab DL.CONTEXT:Bisphosphonates have been widely used in the treatment of osteoporosis. Uncommon side effects have emerged in postapproval use. Because bisphosphonates accumulate in bone and are released for months or years after treatment is stopped, it is reasonable to consider the clinical question of how long to treat.OBJECTIVE:In this personal perspective, we review the pharmacology and mechanism of action of bisphosphonates and the clinical studies that support their efficacy. We then review the literature for longer-term studies and reports of possible side effects that were not seen in clinical trials.RESULTS:Bisphosphonates have demonstrated antifracture efficacy in randomized, placebo-controlled trials of 3 and 4 yr duration and have been widely used since the initial release of alendronate in For zoledronic acid and risedronate, an early effect (fractures reduced within 6-12 months of starting therapy) has been shown. A sustained effect for risedronate has been shown through 5 yr and suggested through 7 yr. Ten-year data with alendronate and 8 yr data with risedronate indicated good tolerability and safety; it is unlikely that longer-term studies will be done. Side effects that emerged in clinical trials include esophageal irritation with oral administration and acute phase response with iv treatment or high-dose oral therapy. Uncommon side effects that have been noted with wide clinical use include osteonecrosis of the jaw, musculoskeletal complaints, and atypical fractures. The numbers of events are small, and a clear cause-and-effect relationship between these events and bisphosphonate treatment has not been established. Because bisphosphonates accumulate in bone, they create a reservoir leading to continued release from bone for months or years after treatment is stopped. Studies with risedronate and alendronate suggest that if treatment is stopped after 3-5 yr, there is persisting antifracture efficacy, at least for 1-2 yr.CONCLUSIONS:Bisphosphonates are popular and effective for treatment of osteoporosis. Because they accumulate in bone and provide some residual antifracture reduction when treatment is stopped, we recommend a drug holiday after 5-10 yr of bisphosphonate treatment. The duration of treatment and length of the holiday are based on fracture risk and pharmacokinetics of the bisphosphonate used. Patients at mild risk might stop treatment after 5 yr and remain off as long as bone mineral density is stable and no fractures occur. Higher risk patients should be treated for 10 yr, have a holiday of no more than a year or two, and perhaps be on a nonbisphosphonate treatment during that time.Porras AG, et al. Clin Pharmacokinet. 1999;36(5):Watts NB, et al. J Clin Endocrinol Metab. 2010;95(4):28
29 Long-term Experience with Alendronate Fit Long-term Extension (FLEX) Study Patients who received ~5 years of alendronate in the Fracture Intervention Trial signed up for a second 5-year studyRe-randomized to stay on alendronate (n = 662) or changed to placebo (n = 437)For those who had 10 years of alendronate compared with stopping after 5 yearsClinical vertebral fractures were reduced by 55% overallNonvertebral fractures were reduced by 50% in women with T-scores -2.5 or below at the start of FLEXSchwartz AV, et al. J Bone Miner Res. 2010;25:29
30 Clinical Vertebral Fractures in the FLEX Study 65.3%ALN 5 years Placebo 5 years5Alendronate 10 years4RR 55%P = 0.013Cumulative Incidenceof Fractures (%)32.4%21the message in the oval is that fracture risk is similar for the first 2 years after stopping therapy vs continuing treatment.12345Years Since FITALN/PLBALN/ALNBlack DM, et al. JAMA. 2006;296:30
31 Suggestions for Bisphosphonate Duration Long-term treatment (e.g., 5–10 years) appears to be safe for most patientsFor lower risk patients, after 3–5 years of treatment, “drug holidays” can probably be taken without a major sacrifice of efficacyHigher risk patients should probably continue treatment for at least 10 yearsNo evidence beyond 10 yearsWatts NB and Diab D. J Clin Endocrinol Metab. 2010;95(4):
32 DenosumabFully human monoclonal antibody to RANKL; decreases osteoclast differentiation, function and survivalReduces risk of spine, hip and nonvertebral fracturesFor treatment of osteoporosis, SQ dosing every 6 monthsDoes not require dose adjustment for decreased kidney functionEffect is reversible within 6–12 months of stoppingDenosumab is a fully human monoclonal antibody with a unique mechanism of action that binds with high affinity to, and inhibits the activity of human RANK (receptor activator of nuclear factor kappa B) ligand, the primary mediator of osteoclast activity1. Amgen scientists have confirmed the essential role of RANK Ligand pathway in the formation, activation and survival of osteoclasts, the cells that are associated with bone resorption1,2. Since RANK Ligand is part of the TNF receptor superfamily, high specificity is demonstrated by the fact that denosumab does not bind to other TNF receptors.1 The pharmacokinetics (SC administration) of denosumab in postmenopausal women were nonlinear with dose. The serum profiles were characterized by three distinct phases: 1) a prolonged absorption phase, which resulted in maximum serum concentrations that increased disproportionately greater (2.6-fold) than the increase in dose and were observed between 5 and 21 days after administration; 2) a prolonged -phase, characterized by half-lives that increased with dose to a maximum of 32 days; and 3) a more rapid terminal phase observed at concentrations <1,000 ng/mL with a half-life that increased from 5 to 10 days as dose increased from 0.01 to 3.0 mg/kg. Because of the nonlinear pharmacokinetics, the mean serum residence time increased with dose from 12 to 46 days.11. Bekker PJ, et al. A single-dose placebo-controlled study of AMG-162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:2. Boyle WJ, et al. Osteoclast differentiation and activation. Nature. 2003;423:3. Peterson HC, et al. AMG 162 maintains serum concentrations for up to 9 months following a single subcutaneous dose in healthy postmenopausal women. J. Bone Miner. Res. 2003; 18(Suppl 2):S166. Abstract SA393 ad poster.Cummings SR, et al; FREEDOM Trial. N Engl J Med. 2009;361(8):Jiang X, et al. Menopause. 2013;20(2):
33 Differences Among Antiresorptive Agents Pharmacology – mechanism of action, onset and offset of effect, skeletal retentionRoute of administration – oral (fasting or with food) or parenteralFrequency of administration – daily, weekly, monthly, quarterly, twice yearly, once yearlySide effects/tolerability – depends on agent and patientNon-skeletal effects – breast cancer reduction (raloxifene)Cost/insurance coverage – generic oral; drugs “administered by health professional” covered by Medicare Part B
34 Teriparatide Recombinant human PTH (rhPTH [1-34]) Mechanism of action different from other agents (anabolic)Daily SC injectionIndicated for patients at high risk for fracturePostmenopausal women with osteoporosisMen with primary or hypogonadal osteoporosisMen and women with osteoporosis associated with sustained systemic glucocorticoid therapyTreatment limited to 2 years, follow with antiresorptive agentForteo PI. Accessed Feb 2013.Han SL, Wan SL. Int J Clin Pract. 2012;66:
35 Monitoring Monitor with DXA every 1–2 years Do not "over-interpret" changeBe happy when BMD is stable OR increasingWhy do some patients lose BMD on treatment?Poor adherenceMalabsorptionUnderlying disorders that need to be addressedSome patients may respond to therapy yet still have unacceptably high fracture risk – consider change in therapy
36 Fall Prevention Improve lighting Remove loose rugs Add grab bars near bathtubs, toilets and stairwaysFormal home safety evaluationPhysical therapy for core strength and balanceEliminate medications that can affect alertness and balanceAssistive device evaluation and trainingSweet MG, et al. Am Fam Physician. 2009;79(3):
37 Where Are We Now? The Good News Improved awarenessExcellent diagnostic tools availableFracture risk assessment using BMD and/or clinical risk factorsSafe and effective individualized treatmentBetter understanding of pathogenesisFederal initiatives to improve care
38 Where Are We Now? The Bad News Declining numbers of patients on therapyUnder-recognition of patients at risk for fracturePoor primary and secondary adherencePoor patient understanding of risk/benefitDecreasing access to DXAIncreasing patient concerns about side effects
39 Secondary Fracture Prevention A fracture is a sentinel eventA fracture in a person over 50 is the most powerful risk factor for a future fractureMany high risk patients have the fracture successfully treated but do NOT receive subsequent medical assessment and treatment to prevent the next fracture
40 What can I Do as a PCP? Practical Steps Patient dialogRisk communicationShared decision makingDecision aidsHandoutsWeb resourcesBrochures
41 What can I Do as a PCP? Practical Steps Identify patients who are at high risk Use EHR decision toolsFlag patients with risk profileUse checklist of risk factorsIdentify patients who are not adherentPharmacy refill data if availableAsk questionsPatients who are nonadherent to one therapy are often nonadherent to others
42 Performance-improvement CME and MOC Part IV Approved (ABFM) PI-CME: performance improvement continuing medical educationMOC: maintenance of certificationABFM: American Board of Family MedicineABIM: American Board of Internal Medicine.https://achsos.community360.net/default.aspx. Accessed April 2013.
43 Update on Management of Osteoporosis What is osteoporosis?Decreased bone strength predisposing to an increased risk of fractureWhy you should careCommon, significant cost, morbidity and mortalityWhom to test and howDXA for all women by age 65, higher risk women earlier; FRAX is a useful toolWhom to treat and howIndividuals at high risk of fracture; approved agents are safe and effective; treatment decisions must be individualized43
44 Questionsor Comments?WILL YOUR BONES LAST AS LONG AS YOU DO?