UPDATE ON UPDATE ON OSTEOPOROSIS OSTEOPOROSIS DR. SALIHA ISHAQ, MBBS, MD. DR. SALIHA ISHAQ, MBBS, MD. American Board of Internal Medicine & Rh eumatology. American Board of Internal Medicine & Rheumatology. Assistant Professor Assistant Professor Department of Medicine Department of Medicine Aga Khan University Hospital Aga Khan University Hospital
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DR. SALIHA ISHAQ, MBBS, MD.DR. SALIHA ISHAQ, MBBS, MD.American Board of Internal Medicine & Rheumatology.American Board of Internal Medicine & Rheumatology.
Assistant ProfessorAssistant Professor
Department of MedicineDepartment of MedicineAga Khan University HospitalAga Khan University Hospital
Osteoporosis Is a Chronic,Osteoporosis Is a Chronic,
Progressive Disease withProgressive Disease with
Potentially SeriousPotentially Serious
ConsequencesConsequences Women withWomen with
postmenopausalpostmenopausalosteoporosis canosteoporosis can
have fractures withhave fractures withminimal traumaminimal trauma11
– 1 in 2 women > 50 will1 in 2 women > 50 willexperience an osteoporoticexperience an osteoporoticfracture in their remainingfracture in their remaininglifetimelifetime22
– In 2005, incidence of In 2005, incidence of osteoporotic fractures in womenosteoporotic fractures in women≥≥ 50 was more than 1.4 million50 was more than 1.4 million33
– 1 in 5 patients who have a1 in 5 patients who have ahip fracture will die within ahip fracture will die within ayearyear44
Image courtesy of Geoffrey B. Higgs, MD.1. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 20082. US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. 2004.3. Burge R, et al. J Bone Miner Res. 2007;22:465-475.4. Johnell O, et al. Osteoporos Int . 2004;15:38-42.5
Decreased estrogen results in increased osteoclasticDecreased estrogen results in increased osteoclastic
activity without increased osteoblastic activityactivity without increased osteoblastic activity Bone loss – 2-3% per year of total bone mass (over aBone loss – 2-3% per year of total bone mass (over a
life time a women may loose up to 40% of her peaklife time a women may loose up to 40% of her peakbone mass.)bone mass.)
Most common fx: vertebral, distal forearmMost common fx: vertebral, distal forearm
Age relatedAge related – 3– 3rdrd decade of life starts slowdecade of life starts slowdecline in bone mass at rate of 0.5-1% per yeardecline in bone mass at rate of 0.5-1% per year Most common types of fx: hip and radiusMost common types of fx: hip and radius F>MF>M
World Health OrganizationWorld Health Organization
(WHO) Definition(WHO) Definition
Based on BMD testingBased on BMD testing
Normal: T score above –1Normal: T score above –1
Osteopenia: T score between –1 and –2.5Osteopenia: T score between –1 and –2.5
Osteoporosis: T score at or below –2.5Osteoporosis: T score at or below –2.5
Severe osteoporosisSevere osteoporosis:: T score –2.5 orT score –2.5 orlower in the presence of 1 or morelower in the presence of 1 or morefracturesfractures
Dual –energy x-ray absorptiometryDual –energy x-ray absorptiometry (DXA or DEXA).(DXA or DEXA).
Gold StandardGold Standard
Measures BMD in spine, hip, or wristMeasures BMD in spine, hip, or wrist
Completed in a few minutesCompleted in a few minutes
Radiation exposure less than 1/10 of standard x-rayRadiation exposure less than 1/10 of standard x-ray Ultrasound densitometryUltrasound densitometry No radiatiation exposureNo radiatiation exposure
Measures BMD in heel, patellaMeasures BMD in heel, patella
Cost-effectiveCost-effective
Poor correlation between US and DXAPoor correlation between US and DXA
Inconsistent young normal reference populations may contributeInconsistent young normal reference populations may contribute
Foundation (NOF) GuidelinesFoundation (NOF) Guidelines
All postmenopausal women under age 65 whoAll postmenopausal women under age 65 whohave one or more additional risk factors forhave one or more additional risk factors for
osteoporotic fx (besides menopause)osteoporotic fx (besides menopause)
All woman aged 65 and older regardless of All woman aged 65 and older regardless of additional risk factorsadditional risk factors
Postmenopausal women who present withPostmenopausal women who present withfracturesfractures
All men above the age of 70All men above the age of 70
Available Medications forAvailable Medications for
PostmenopausalPostmenopausal
OsteoporosisOsteoporosis
Oral bisphosphonates are the most commonly usedpharmacologic agents for osteoporosis management2
Oral and IVBisphosphonates
Anabolic Agent1
EstrogenAgonist/Antagonist
Estrogen*
Calcitonin
*Indicated for prevention only; PTH = parathyroid hormone1. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2008.2. IMS Health NSP Data. Analysis of PMO product basket. January 2009.
Current updateCurrent update 12001200 800–1000800–1000
“NOF revised its recommendations after careful consideration and review of a growing body of evidence that calcium and vitamin D3 deficiency is widespread throughout the world as well as in
the US, particularly in adults 50 and older.”
NOF Scientific Statement, Revised October 2008
Adapted from National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. National Osteoporosis Foundation, 2003; National OsteoporosisFoundation. National Osteoporosis Foundation’s updated recommendations for calcium andvitamin D intake. Available at: www.nof.org/prevention/calcium_and_VitaminD.htm. Accessed 26 January 2009.
Number of patientsNumber of patients 12551255 : Most patients had 1–5 Vertebral Fx at baseline (n = 926 of 1: Most patients had 1–5 Vertebral Fx at baseline (n = 926 of 1
378 actually completed the study378 actually completed the study
Mean AgeMean Age 68 (postmenopausal)68 (postmenopausal)
DrugDrug Placebo (n = 311), 100 IU (n = 316), 200 IUPlacebo (n = 311), 100 IU (n = 316), 200 IU(n = 316, marketed dose) or 400 IU (n = 312) Calcitonin(n = 316, marketed dose) or 400 IU (n = 312) Calcitonin
Calcium/Vitamin DCalcium/Vitamin D 1000 mg/400 IU daily1000 mg/400 IU daily
% with Prevalent VFx% with Prevalent VFx 79%79%
Primary EndpointPrimary Endpoint Spine BMD and new VFX in patients withSpine BMD and new VFX in patients withlow bone mass (T < –2.0) and 1–5 new VFXlow bone mass (T < –2.0) and 1–5 new VFX
CALCITONIN NASAL SPRAY THERAPYCALCITONIN NASAL SPRAY THERAPYPREVENT RECURRENCE OF OSTEOPOROTICPREVENT RECURRENCE OF OSTEOPOROTIC
FRACTURES(PROOF)FRACTURES(PROOF)
Chesnut et al: AJM 2000, Vol 109, 267-276Chesnut et al: AJM 2000, Vol 109, 267-276
Accelerated bone loss afterAccelerated bone loss afterstoppingstopping
Increased risk of uterine caIncreased risk of uterine ca(if unopposed)(if unopposed)
Increased risk of Increased risk of thromboembolic eventsthromboembolic events
Possible increased risk of Possible increased risk of breast cancerbreast cancer
Side effects: breastSide effects: breasttenderness, breakthroughtenderness, breakthroughbleedingbleeding
Increased risk of Increased risk of coronary events incoronary events inwomen with known CADwomen with known CADin first year of usein first year of use(HERS trial(HERS trial))
Number of PatientsNumber of Patients 7705 patients (2 subgroups)7705 patients (2 subgroups)
Substudy 1 = 5064 with hip or spine T-scoreSubstudy 1 = 5064 with hip or spine T-score ≤≤ –2.5 Substudy 2 =–2.5 Substudy 2 =2641 with prior VFX2641 with prior VFX
Mean AgeMean Age 67 (postmenopausal)67 (postmenopausal)
DrugDrug 60 mg (marketed dose) or 120 mg raloxifene60 mg (marketed dose) or 120 mg raloxifene
Calcium/Vitamin DCalcium/Vitamin D 500 mg/400 IU daily500 mg/400 IU daily
Primary EndpointPrimary Endpoint VFX and non-VFX in patients with low bone mass (T-score < –2.5)VFX and non-VFX in patients with low bone mass (T-score < –2.5)or radiographic VFXor radiographic VFX
::RALOXIFENERALOXIFENE
MULTIPLE OUTCOMES OF RALOXIFENE EVALUATIONMULTIPLE OUTCOMES OF RALOXIFENE EVALUATION
increased vertebral and femoralincreased vertebral and femoral
bone densitybone density
PTH (2 0 µg) PTH (40 µg)
Spine . %9 7 . %1 3 7
Hip . %2 8 . %5 1
Percent change from baseline over a 19 monthPercent change from baseline over a 19 monthfollowup period (length of randomization)followup period (length of randomization)
Its an anti RankL drug approved by FDA for post menopausalIts an anti RankL drug approved by FDA for post menopausalOsteoporosis.Osteoporosis.
AntiSclerostin:AntiSclerostin:
Sclerostin is produced by Osteocytes of a person who hasSclerostin is produced by Osteocytes of a person who hasinactive lifestyle. It blocks the of Wntinactive lifestyle. It blocks the of Wntββ / Catenin pathway,/ Catenin pathway,so reduced the bone formation. Anti sclerostin is soonso reduced the bone formation. Anti sclerostin is soonavailable for Osteoporosis treatment.available for Osteoporosis treatment.
Anti Cathepsin K: BaticalibAnti Cathepsin K: Baticalib
Cathepsin K is an Enzyme produced by Osteoclast, necessaryCathepsin K is an Enzyme produced by Osteoclast, necessaryfor bone resorption. Anti Cathepsin K is an oral drugfor bone resorption. Anti Cathepsin K is an oral drug
Fully human monoclonal antibody-IgGFully human monoclonal antibody-IgG22 isotypeisotype
High affinity and specificity for human RANK ligandHigh affinity and specificity for human RANK ligand Does not bind to TNFα, TNFβ, TRAIL, or CD40LDoes not bind to TNFα, TNFβ, TRAIL, or CD40L Pharmacokinetics (SC): similar to other fully human IgGPharmacokinetics (SC): similar to other fully human IgG
22
monoclonal antibodiesmonoclonal antibodies– Absorption is rapid and prolonged (CAbsorption is rapid and prolonged (Cmaxmax ≈1–4 wks postdose)≈1–4 wks postdose)
– Long half-life ≈34 days with maximum doseLong half-life ≈34 days with maximum dose
– Distribution ≈ intravascular volumeDistribution ≈ intravascular volume
– Clearance ≈ reticuloendothelial systemClearance ≈ reticuloendothelial system
– No kidney filtration or excretion of intact moleculeNo kidney filtration or excretion of intact molecule