Osteoporosis is a disease that simply can’t be ignored. The statistics are mind boggling ! In USA alone there are 10 million ppl….. Out of which 80 % are women. Also about 10 % of US population ( 33 million) have weak bones i.e. osteopenia.
Here we can see the immense fracture risk ass. with the disease. More than 2 million fractures occur per year in patients with either osteo…or osteo… Out of which majority are vertebral # f/b hip # f/b pelvic #.
Out of these 3, maximum morbidity and mortality is assoc. with hip #. As you can see after sustaining hip #, half of the people loose their mobility and a quarter loose skills to live independently. A recent metaanalysis showed increase in rate of death by 5- 8 times after a hip #.
This graph shows the relevance of recognizing osteoporosis as a major disease. As you can clearly see it far out numbers the other 3 major illnesses.
Coming to the definition , This disease has three components: loss of mass and architecture and fragility . Who DEFINES OSTEOPOROSIS AS t SCORE OF -2.5 AS DIAGNOSTIC. Definition of t score and z score……?
Following are the risk factors which predispose to osteoporosis: elderly caucasian female, low BMI, h/o personal or parental fracture , rheumatoid arthritis, chronic alcoholic, smoking.
As per the NOF guidelines, the recommendations for screening are women ……
This is the WHO’s fracture risk assessment tool called FRAX which takes into account the prior mentioned risk factors and calculates their 10 year risk of fracture. This is used to guide management of patient's with osteopenia.
So, Who to treat ? As per the NOF guidelines …. For T score b/w -1 to – 2.5, we go by the FRAX risk score.
As we all know calcium and vitamin d are useful for prevention and treatment of osteoporosis. These are the sources rich in calcium and vitamin D. Weight bearing exercise plays an important part in management as well.
This slide gives an overview of different therapeutic strategies for osteoporosis. Bisphosphonates act by inhibiting bone resorption. Many other modalities including estrogen, serms, calcitonin, denosumab act by inhibiting bone resorption.Few of the treatment are aimed at stimulation of bone formation . PTH analog Teriparatide is the only FDA approoved agent which is an anabolic agent.
The mainstay of treatment is bisphosphonates. Alendronate was the first bisphosphonates approved in US f/b rise.., f/b iband…and the most recent one is zoledronate.
The CI include….
There has been considerable discussion about how long to treat with bisphosphonates. This does not come up with other diseases such as HTN, hyperlipidemia. For these diseases, benefits of treatment disappear on stopping drugs. However, Bispho. Accumulate in the bone for years. There is no standard of care on this but numerous opinions exist.. As per one expert opinion, duration should be individualized and should be based on risk factors. Patient with high risk should be treated for 10 years , then a holi……….., Patients who deserve treatment should have min. duration of 5 years , then holiday and resumption of drug depends on risk factors.
ONJ is defined as Exposed necrotic bone in maxillofacial region, not healing > 6-8 weeks with no prior h/o cranio- facial radiation.60 % of the cases have been found to follow dental surgical procedure. Pain/swelling/suppuration/paresthesia/soft tissue ulceration/sinus tracts/loose teeth..The First report came in 2003. These are all post marketing trial . They looked retrospectively in patients in the HORIZON trial, they found one case each in placebo and ZA group.
This slide shows the difference in incidence of ONJ in patient with skeletal mets vs osteoporosis. The reporting rate has been 1 ……….. As compared to patients with malignancy and mets ,in whom incidence is much higher.The main reason behind the difference is that patients with sk mets require higher and more frequent doses/
The risk factors for ONJ are high dose frequent dosing of Iv bisphosphonates as in cancer patients ,patients on chemo/ chronic steroids, dental extraction/ dental surgical procedure , prior periodontal disease ,alcohol/smoking. LONG duration of treatment. poorly fitting dental appliances and intraoral trauma.
Patients should be informed about the risk of developing ONJ, good dental hygiene is recommended. Endodontic treatment is preferred to dental extraction or surgery.
ThThe usual osteoporotic hip # occurs at femoral neck or intertrochanteric site. This atypical fracture has been found to occur below the lesser trochanter and above the supracondylar flare. It may be assoc. with Prodromal groin or thigh pain for weeks to months. This # has characteristic radiological findings…transverse or short oblique, medial cortical spike and cortical hypertrophy
Prolonged tx with BPs decreased structural integrity at the femoral shaft. This corresponds with the occurrence of this type of transverse subtrochanteric fracture clinically. The published and unpublished data reviewed show these atypical fractures occur in less than 1 in 10000 pts and many more fractures are prevented by these medications. The risk-benefit ratio clearly favors treatment with bisphosphonates. ASBMR position statement : The published and unpublished data reviewed show these atypical fractures occur in less than 1 in 10000 pts and many more fractures are prevented by these medications. The risk-benefit ratio clearly favors treatment with bisphosphonates. Patients should be aware of this and report thigh pain and continue current medications as directed. Physicians should also be aware and follow prescribing instructions and report side effects to the FDA.
The HORIZON pivotal trial showed a significant increased incidence of serious a fib. 1.3 % vs 0.5 %. But no statistically sig. Increase in incidence was found in the HORIZON recurrent # trial (small/short study), or FIT or VERT trial. A recent meta analysis did show ass. With risk of serious A fib but no risk of stroke or CV mortality.
Esophageal cancer has been a concern in patients on oral bisphosphonates. Over the past 2 decades, FDA has received 23 case reports from USA. 31 cases from Japan/Europe. Current data do not support a causal ass. b/w oral bisphosphonates $ eso. Ca.
Adverse effects on kidneys after iv infusion depends on peak conc, dose and rate of infusion. Risk is lowered by decreasing rate of infusion and hydrating prior to infusion.
Reduction in bone mass has long dominated the thinking about and approach to the problem of osteoporosis. A now large body of evidence indicates that bone mass is not adequate to explain satisfactorily either the skeletal fragility of osteoporosis or the effects of bone active agents. By contrast, bone remodeling activity seems to provide a better explanation of both. Current theory in the field is shifting to this conclusion. This figure represents a revision of the commonly held hierarchical relationship of factors contributing to osteoporotic fracture risk. It shows an enhanced role for bone remodeling in skeletal fragility and also indicates secondary effects of factors such as nutrition and hormones on bone mass.
14/06/13 04:05 Slide 30: Zoledronic Acid 5 mg Clinical Program The robust clinical development program for zoledronic acid 5 mg includes studies for the treatment of Paget’s disease (core study completed, 1 extension study results forthcoming), postmenopausal osteoporosis, osteogenesis imperfecta, corticosteroid-induced osteoporosis, prevention of recurrent hip fractures, and male osteoporosis. Other additional trials under way are not shown here. Zoledronic acid 5 mg is not approved for postmenopausal osteoporosis, male osteoporosis, corticosteroid-induced osteoporosis, prevention of recurrent hip fracture, or osteogenesis imperfecta, as of 1 March 2006. Reference 1. Reid I, Miller P, Fraser W, et al. Comparison of a single infusion of zoledronic acid with risedronate in Paget’s disease. N Engl J Med. 2005;353:898-908.
Cumulative Risk of Hip Fracture (Strata I & II) ZOL 5 mg reduced the relative risk of incurring a hip fracture over time by 41% compared with placebo (hazard ratio=0.59; P = .0024). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.
Cumulative Risk of Clinical Vertebral Fracture (Strata I & II) Assessment of number of clinical fractures (painful fractures that led to an office evaluation) occurring over 3 years revealed that a single annual infusion of ZOL 5 mg reduced the risk of clinical vertebral fractures by 77% compared with placebo over 3 years ( P < .0001). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.
Cumulative Risk of Clinical Non-vertebral Fracture (Strata I & II) Incidence of clinical non-vertebral fractures was significantly reduced (approximately 25%) over 3 years with ZOL 5 mg treatment compared with placebo ( P = .0002; estimated hazard ratio of 0.75). The most frequent fracture locations were wrist, hip, arm, and rib. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.
14/06/13 04:05 看完臨床的資料後，再來看看從骨鬆患者的角度對於這種一年一次靜脈注射的骨鬆治療的看法，這是 2006 於歐洲 ECCEO 所發表的資料 ： 以下資料就是 Lindsay 等人分別針對骨鬆患者對一週一次口服 alendronate 70 mg (n = 59) 與一年一針的 Zoledronic acid 5 mg (n = 69) 之喜好度進行為期二十四週的研究，每一位患者會在研究結束後，針對下列方便性、滿意度、長期接受意願及喜好程度等四個問題做回答 1 根據這個多中心、隨機、雙盲的研究結果顯示，整體而言將近有 66.4% 的人 (N = 122) 表示比較喜愛一年一針的治療，另有 19.7% 則是比較喜愛一週一次口服治療，至於其他的 13.9% 則無特別的喜好。 因此，不論是從患者的角度，還是從臨床的角度，都支持 Zoledronic acid 5 mg 這種一年一針的 IV 劑型應用於骨鬆治療的潛力，也請各位醫師們可向患者推薦這種創新、又方便的治療，以有效改善患者醫囑性不佳的老問題，因為惟有持續的治療，才能有效控制骨鬆、達到避免骨鬆惡化、預防骨折的目的 ! Reference 1. Lindsay R, Saag K, Kriegman A, Davis J, Beamer E, Zhou W. A single zoledronic acid 5-mg infusion is preferred over weekly 70 mg oral alendronate in a clinical trial of postmenopausal women with osteoporosis/osteopenia. Poster presented at: 6th European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis; March 15-18, 2006; Vienna, Austria.
Osteoporosis diagnosis and treatment
Osteoporosis ManagementOsteoporosis ManagementEfficacy and safety of bisphosphonates
Today’s talk :Today’s talk : Burden of the disease.Burden of the disease. Screening and treatment guidelines.Screening and treatment guidelines. Bisphosphonates.Bisphosphonates. Once yearly bisphoshonateOnce yearly bisphoshonate Controversial topics : Association ofControversial topics : Association ofbisphosphonates withbisphosphonates with ONJONJ Atypical femoral fracturesAtypical femoral fractures Atrial fibrillation.Atrial fibrillation. Esophageal cancer.Esophageal cancer.
Burden of DiseaseBurden of Disease2.52.5 million people in Indonesiamillion people in Indonesiahave Osteoporosishave Osteoporosis88 million people in Indonesiamillion people in Indonesiahave Osteopenia.have Osteopenia.
Burden of DiseaseBurden of Disease> 0,5 million> 0,5 millionfractures/year due to either.fractures/year due to either.75,00075,000 HIP fractures.HIP fractures.150,000150,000 vertebral fractures.vertebral fractures.35,00035,000 pelvic factures.pelvic factures.Bone health and osteoporosis: Department ofBone health and osteoporosis: Department of
Burden of Disease :Burden of Disease :Hip fracturesHip fractures ::50 %50 % Permanent impairedPermanent impairedmobility.mobility.25 %25 % Loose skills to liveLoose skills to liveindependently.independently.Increased all cause mortality : firstIncreased all cause mortality : first 33monthsmonths after hip fracture.after hip fracture.1.2010 position statement of the North American Menopause Society. Menopause 2010.1.2010 position statement of the North American Menopause Society. Menopause 2010.
Vertebral FracturesSemi-quantitative reading / visual scoringGenant et al., J Bone Miner Res 1993, 8:137Normal(Grade 0)Wedge fracture Biconcave fracture Crush fractureMild fracture(Grade 1, ~20-25%)Moderate fracture(Grade 2, ~25-40%)Severe fracture(Grade 3, ~40%)
Who to screenWho to screen Women > 65 years.Women > 65 years. Men > 70 years.Men > 70 years. Postmenopausal women /men >50 yearsPostmenopausal women /men >50 yearswith clinical risk factors.with clinical risk factors. H/o fracture at age > 50 years.H/o fracture at age > 50 years. Chronic steroid use.Chronic steroid use.
Direct measurement of BMD by DXA andas well as CT allows us to diagnose osteopenia
Who to treat ?Who to treat ?Prior h/o hip/vertebral #Prior h/o hip/vertebral #ororT Score < -2.5T Score < -2.5ororT Score -1 to -2.5 &10 yr risk (FRAX) :HIP # > 3 % ormajor osteoporotic # > 20 %T Score -1 to -2.5 &10 yr risk (FRAX) :HIP # > 3 % ormajor osteoporotic # > 20 %Postmenopausal women /men > 50 yrswith
Recommendation for women and men > 50 yoRecommendation for women and men > 50 yo•• Counsel on the risk of osteoporosis and related fractures.Counsel on the risk of osteoporosis and related fractures.•• Advise on a diet rich inAdvise on a diet rich in fruits and vegetablesfruits and vegetables and that includesand that includesadequate amounts of totaladequate amounts of total calcium intakecalcium intake (1,000 mg per day(1,000 mg per dayfor men 50-70; 1,200 mg per day for women 51 and olderfor men 50-70; 1,200 mg per day for women 51 and olderand men 71 and older).and men 71 and older).•• Advise onAdvise on vitamin Dvitamin D intake (800-1,000 IU per day), includingintake (800-1,000 IU per day), includingsupplements if necessary for individuals age 50 and older.supplements if necessary for individuals age 50 and older.•• Recommend regularRecommend regular weight-bearing and muscle-strengtheningweight-bearing and muscle-strengtheningexercise to improve agility, strength, posture and balance andexercise to improve agility, strength, posture and balance andreduce the risk of falls and fractures.reduce the risk of falls and fractures.
••AssessAssess risk factorsrisk factors for falls and offerfor falls and offerappropriate modifications :appropriate modifications : home safety assessment,home safety assessment, balance training exercises,balance training exercises, correction of vitamin D insufficiency,correction of vitamin D insufficiency, avoidance of certain medications andavoidance of certain medications and bifocals use when appropriatebifocals use when appropriate
Treatments & EfficacyVertebral Fx Non-vertebral FxOther Fx Hip FxOralHRT Yes Yes YesEtidronate* YesAlendronate* Yes Yes YesRisedronate* Yes Yes YesIbandronate* Yes [Yes]Raloxifene* YesCalcitriol* YesStrontium Ranelate* Yes Yes [Yes]
Vertebral Fx Non-vertebral FxOther Fx Hip FxSubcutaneousTeriparatide* Yes Yes1-84 PTH* YesDenosumab* Yes Yes YesIntravenousPamidronateIbandronate*Zoledronate* Yes Yes YesIntranasal or SubcutaneousCalcitonin* Yes
Vertebral Fx Nonvertebral FxOther Fx Hip FxAlendronate* Yes Yes YesRisedronate* Yes Yes YesZoledronic acid* Yes Yes YesPTH* Yes Yes ???Strontium ranelate* Yes Yes ???Denosumab* Yes Yes YesAppropriate use of appropriate treatmentsAppropriate use of appropriate treatmentscan halve the incidence of fracturescan halve the incidence of fractures* plus calcium + vitaminD
Mainstay ofMainstay of treatmenttreatment ::BisphosphonatesBisphosphonatesApproval in US for osteoporosisApproval in US for osteoporosis Alendronate : 1995Alendronate : 1995 Risedronate : 2000Risedronate : 2000 Ibandronate : 2005Ibandronate : 2005 Zoledronate : 2007.Zoledronate : 2007.
Atypical fracturesAtypical fractures ? Long term over suppression of bone? Long term over suppression of boneturnover.turnover. Incidence : 1 in 10,000.Incidence : 1 in 10,000. Associated median treatment duration : 7Associated median treatment duration : 7years.years. Causality : long term bp/ atypical #Causality : long term bp/ atypical #unproven.unproven. Further large scale studies needed.Further large scale studies needed.
RecommendationsRecommendations Educate physician/patient aboutEducate physician/patient aboutProdromal pain.Prodromal pain. Evaluate with urgent X-Ray.Evaluate with urgent X-Ray. If negative, may consider MRI.If negative, may consider MRI. Stop BP’s if atypical fracture confirmed.Stop BP’s if atypical fracture confirmed.
Atrial fibrillationAtrial fibrillation FDA recommends physiciansFDA recommends physicians to not alterto not altertheir prescribing patterntheir prescribing patterns while it continuess while it continuesto monitor post marketing reports of AF into monitor post marketing reports of AF insuch patients.such patients. In v/o above and absence of definitiveIn v/o above and absence of definitivedata : Benefits of treatment outweigh risks.data : Benefits of treatment outweigh risks.
Esophageal cancerEsophageal cancer 23 cases reported in last 223 cases reported in last 2decades. (Wysowski et al)decades. (Wysowski et al) 31 cases from31 cases fromEurope/Japan.Europe/Japan. Median time from use toMedian time from use todiagnosis : 1-2 yr.diagnosis : 1-2 yr. Time from exposureTime from exposureinconsistent w/ causalinconsistent w/ causalrelation.relation. Further studies neededFurther studies needed..
Renal safetyRenal safety Safe for creatinine clearance > 30 -35 mlSafe for creatinine clearance > 30 -35 ml/min./min. Lack of experience < 30 ml/min.Lack of experience < 30 ml/min. No data for use in ESRD.No data for use in ESRD. Exact bone disease unknown unless biopsy.Exact bone disease unknown unless biopsy. Expert opinion: half the dose could be usedExpert opinion: half the dose could be usedfor 3 years in ESRD once bone biopsyfor 3 years in ESRD once bone biopsyconfirms osteoporosis.confirms osteoporosis.
FractureBoneStrengthMaterialPropertiesRemodelingFallsShape &ArchitectureExercise &LifestyleHormonesNutritionBoneMassPosturalReflexesSoft TissuePaddingReproduced with permission from Heaney RP. Bone 33:457-465, 2003Factors Leading to Osteoporotic Fracture:Role of Bone Remodeling2004
HIP FRACTURE – Female Age 75 and overGive single oral dose 100,000 IU vitaminD @ as soon as feasible post hip fracture & start 1000mgCaCO3+800IU vitaminD asap, (if on this already – continue)Already on a BP(bisphosphonate)?NoYesGood prognosis & eGFR 30 or overDuration of treatment?Yes No1. Patient or resident carer understandconcepts of osteoporosis, fracture riskreduction & protocol for ingesting oral BPAND2. No contraindications to oral BPs[dysphagia / oesophageal stricture /achalasia /hypocalcaemia].YesOral ALN 70mg / wkNoPatient suitable for IV BP& eGFR 35 or overYes NoArrange IV zoledronic acid 5mginfusion (over at least 15min),4-6/52 after hip fractureConsider oral BP or, if at riskequivalent to that of fractureplus T-score -2.4 or less,consider strontium ranelate.Continue b.d. calcium + vitaminDContinue b.d.oral calcium + vitaminDMore than 2yr 2yr or lessOptimal compliance with / adherenceto BP & BP well toleratedYesNoContinue oral BPIF eGFR is 30 or moreOtherwise continueb.d. calcium + vitaminDGREATER GLASGOW & CLYDE PROTOCOL FOR FRACTURE SECONDARY PREVENTION AFTER HIP FRACTURE IN WOMEN AGE 75+
Once Yearly Zoledronic AcidOnce Yearly Zoledronic AcidReduces FracturesReduces FracturesHORIZON Pivotal Fracture TrialMulti-national, multi-center, RCT7,736 women age 65-89 with T-score <-2.5 or fracture plus T-score < -1.5Calcium 1000-1500 mg/day vit D (400-1200 IU/day)Zoledronic acid IV infusion 5 mglack et al. NEJM 356:1809-1822, 2007
ZOLZOL reducesreduces hiphip fracturefracture*Relative risk reduction (95% confidence interval) vs placeboBlack et al. NEJM 356:1809-1822, 2007P = .00241230Placebo (n = 3861)ZOL 5 mg (n = 3875)CumulativeIncidence(%)Time to First Hip Fracture (months)0 3 6 9 12 15 18 21 24 27 30 33 3641%*(17%, 58%)
P < .0001CumulativeIncidence(%)Time to First Clinical Vertebral Fracture (months)0 3 6 9 12 15 18 21 24 27 30 33 3677%(63%, 86%)Placebo (n = 3861)ZOL 5 mg (n = 3875)1230ZOLZOL reducesreduces vertebralvertebralfxfx*Relative risk reduction (95% confidence interval) vs placeboBlack et al. NEJM 356:1809-1822, 2007
P = .0002Time to First Clinical Non-vertebral Fracture (months)246810120 3 6 9 12 15 18 21 24 27 30 33 3625%(13%, 36%)Placebo (n = 3861)ZOL 5 mg (n = 3875)0CumulativeIncidence(%)ZOLZOL reducesreduces non-vertebralnon-vertebralfxfx*Relative risk reduction (95% confidence interval) vs placeboBlack et al. NEJM 356:1809-1822, 2007
Zoledronic Acid will ImproveZoledronic Acid will Improve PatientPatientCompliance asCompliance as Once-Yearly IV Therapy isOnce-Yearly IV Therapy isPreferredPreferredData from Lindsay R, et al. Poster presented at ECCEO6; March 15-18, 2006; Vienna, Austria.16.418.9Both Are EqualOnce-Yearly IVOnce-Weekly PillMore convenientMore willing totake long termOverallpreferenceN = 12266.459.80 20 40 60 80 10068.066.415.618.020.515.619.713.9% of PatientsMoresatisfying
Take home pointsTake home points Osteoporosis :Osteoporosis : significant burden of diseasesignificant burden of disease.. Main stay treatment :Main stay treatment : bisphosphonatesbisphosphonates.. ? Duration of treatment : individualized.? Duration of treatment : individualized. Patient compliancePatient compliance Patient educationPatient education once yearly IV BPonce yearly IV BP More research needed to confirm associationMore research needed to confirm associationwith ONJ, Sub trochanteric fracture.with ONJ, Sub trochanteric fracture. Benefits of treatmentBenefits of treatment outweigh risks inoutweigh risks inosteoporosis.
Thank youThank youKeep your bone healthyKeep your bone healthy