UPDATE ON OSTEOPOROSIS

DR. SALIHA ISHAQ, MBBS, MD.
American Board of Internal Medicine & Rheumatology. Assistant Professor Department of Medicine Aga Khan University Hospital

Impact        Chronic pain Height loss Kyphosis Decreased selfesteem Restrictive lung dx Constipation. abdominal pain Depression .

Progressive Disease with Potentially Serious Consequences  Women with postmenopausal osteoporosis can have fractures with minimal trauma1 – 1 in 2 women > 50 will experience an osteoporotic fracture in their remaining lifetime2 In 2005. Osteoporos Int. et al. 2004. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 1.4 million3 1 in 5 patients who have a hip fracture will die within a year4 – – 5 Image courtesy of Geoffrey B. Johnell O. et al. Burge R.22:465-475.Osteoporosis Is a Chronic. 2008 2. MD. National Osteoporosis Foundation. US Department of Health and Human Services. 4. Higgs. Bone Health and Osteoporosis: A Report of the Surgeon General. incidence of osteoporotic fractures in women ≥ 50 was more than 1. J Bone Miner Res. 2004. 3.15:38-42. . 2007.

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Risk Factors for Osteoporosis       Non-modifiable Age Race (Caucasian. anticonvulsants.excess thyroxine) . Asian) Female gender Early menopause (<45 y/o) Slender build (<127 lbs) Positive family history         Modifiable Low calcium intake Low vitamin D intake Estrogen/androgen deficiency Sedentary lifestyle Cigarette smoking Alcohol excess (>2 drinks/day) Caffeine excess (> cups/day) Medications (glucocorticoids.

Classification  Primary  Postmenopausal    Decreased estrogen results in increased osteoclastic activity without increased osteoblastic activity Bone loss – 2-3% per year of total bone mass (over a life time a women may loose up to 40% of her peak bone mass.) Most common fx: vertebral.5-1% per year   Most common types of fx: hip and radius F>M 8 . distal forearm  Age related – 3rd decade of life starts slow decline in bone mass at rate of 0.

Bone Mass in Women Over the Lifecycle Percent Peak Bone Mass 100 80 60 Attainment of peak bone mass Peak bone mass Menopaus e Bone loss 40 20 Formation > Resorption Resorption > Formation 9 0 10 20 30 Age (years) 40 50 60 70 80 .

.Bone Growth Overtime Graphic used with permission from The 2004 Surgeon General’s Report on Bone Health and Osteoporosis: What It Means To You.

PBC Thalessemia Thyrotoxicosis 11 .Secondary Osteoporosis Disease states             Acromegaly Addison’s disease Amyloidosis Anorexia COPD Hemochromatosis Hyperparathyroidism Lymphoma and leukemia Malabsorption states (Celiac sprue)     Multiple myeloma Multiple sclerosis Rheumatoid arthritis Sarcoidosis Severe liver dz. esp.

Secondary Osteoporosis Drugs Aluminum  Anticonvulsants  Excessive alcohol) (more than 3 units a day)  Excessive thyroxine  Depo Provera (decreased bone mass reversible after stopping medication)      Glucocorticoids GnRH agonists Heparin Lithium 12 .

5 Osteoporosis: T score at or below –2.World Health Organization (WHO) Definition Based on BMD testing  Normal: T score above –1 Osteopenia: T score between –1 and –2.5 Severe osteoporosis: T score –2.5 or lower in the presence of 1 or more fractures    13 .

patella Cost-effective Poor correlation between US and DXA Inconsistent young normal reference populations may contribute    Single-energy x-ray absorptiometry and peripheral dual x-ray Quantitative computed tomography (QCT) Radiographic absorptiometry 14 . or wrist  Completed in a few minutes  Radiation exposure less than 1/10 of standard x-ray Ultrasound densitometry No radiatiation exposure     Measures BMD in heel.Types of BMD testing    Dual –energy x-ray absorptiometry (DXA or DEXA).  Gold Standard  Measures BMD in spine. hip.

When to perform a bone density test National Osteoporosis Foundation (NOF) Guidelines  All postmenopausal women under age 65 who have one or more additional risk factors for osteoporotic fx (besides menopause) All woman aged 65 and older regardless of additional risk factors Postmenopausal women who present with fractures All men above the age of 70    15 .

Available Medications for Postmenopausal Osteoporosis Antiresorptive Agents1 Oral and IV Bisphosphonates Estrogen Agonist/Antagonist Estrogen* Calcitonin Anabolic Agent1 PTH analog Oral bisphosphonates are the most commonly used pharmacologic agents for osteoporosis management2 16 *Indicated for prevention only. 2. National Osteoporosis Foundation. PTH = parathyroid hormone 1. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Analysis of PMO product basket. January 2009. IMS Health NSP Data. 2008. .

Preventive Measures    Treatment Calcium Vitamin D (400-800 IU) Regular weight bearing exercise  Weight lifting. salsa dancing. jogging. tennis    Smoking cessation Minimize alcohol intake Fall prevention esp for elderly 17 . walking.

National Osteoporosis Foundation. particularly in adults 50 and older. Accessed 26 January 2009. National Osteoporosis Foundation’s updated recommendations for calcium and vitamin D intake.htm.org/prevention/calcium_and_VitaminD.” —NOF Scientific Statement. 2003. Physician’s Guide to Prevention and Treatment of Osteoporosis. .nof. National Osteoporosis Foundation. Revised October 2008 Adapted from National Osteoporosis Foundation. Available at: www.NATIONAL OSTEOPOROSIS FOUNDATION: UPDATED RECOMMENDATIONS Recommended Intake for Adults ≥50 Years Calcium Previous (2003) 1200 (mg/day) Vitamin D3 (IU/day) 400–800 Current update 1200 800–1000 “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.

Sources of Calcium     Dietary – 8oz milk or yogurt = 300mg – 2oz cheese = 400mg Calcium carbonate – Ingest with meals – Generic = 200-600mg – Caltrate = 600mg – TUMS Ultra = 400mg Calcium citrate – Citrical = 500mg Calcium gluconate – Generic = 60mg * All above values represent mg of elemental calcium 19 .

0) and 1–5 new VFX Chesnut et al: AJM 2000.CALCITONIN NASAL SPRAY THERAPY PREVENT RECURRENCE OF OSTEOPOROTIC FRACTURES(PROOF) 1255 Number of patients Mean Age Study Design Drug Calcium/Vitamin D % with Prevalent VFx Primary Endpoint : Most patients had 1–5 Vertebral Fx at baseline (n = 926 of 1 378 actually completed the study 68 (postmenopausal) 5 year. randomized. 100 IU (n = 316). placebo-controlled Placebo (n = 311). Vol 109. double-blind. marketed dose) or 400 IU (n = 312) Calcitonin 1000 mg/400 IU daily 79% Spine BMD and new VFX in patients with low bone mass (T < –2. 200 IU (n = 316. 267-276 .

267-276 .EFFECT OF NASAL CALCITONIN ON RISK OF VERTEBRAL FRACTURES Women withDecreased Dose new fractures risk p<0.05? Placebo 100 IU 200 IU 400 IU 26% 22% 18% 22% 15% 33% 16% No Yes No PROOF Lost 59% of participants to follow-up! Chesnut et al: AJM 2000. Vol 109.

Treatment Estrogen Replacement Therapy (ERT)

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Indication: Used to prevent and treat osteoporosis (FDA indication is for prevention) Mechanism: Decreases osteoclast activity Dose: Estrogen: 0.625mg qd, 0.3mg offers bone protection as well; Progesterone 2.5mg qd (if uterus present)

HRT

Advantages  Increases bone density (1-5%) and decreases risk of fracture (25%)  Relief of hot flashes, vaginal dryness  Decreases LDL, increases HDL  ?Prevention of Alzheimer’s disease  Relatively inexpensive

Disadvantages  Accelerated bone loss after stopping  Increased risk of uterine ca (if unopposed)  Increased risk of thromboembolic events  Possible increased risk of breast cancer  Side effects: breast tenderness, breakthrough bleeding  Increased risk of coronary events in women with known CAD in first year of use (HERS trial)

RALOXIFENE

7. randomized. August 18. 1999--Vol 282.MULTIPLE OUTCOMES OF RALOXIFENE EVALUATION (MORE) Number of Patients 7705 patients (2 subgroups) Substudy 1 = 5064 with hip or spine T-score ≤ –2. No.5) or radiographic VFX EVALUATING THE EVIDENCE: RALOXIFENE Mean Age Mean FN T-Score Study Design Drug Calcium/Vitamin D Primary Endpoint JAMA.5 Substudy 2 = 2641 with prior VFX 67 (postmenopausal) -3. double-blind. placebo-controlled 60 mg (marketed dose) or 120 mg raloxifene 500 mg/400 IU daily VFX and non-VFX in patients with low bone mass (T-score < –2. pp 637-645 .2 SDs 3 year.

Effect of Raloxifene in Women with or Without Pre-Existing Fractures MORE Trial—3 Years Placebo Raloxifene 60 mg/d 25 % of Women with Incident Vertebral Fractures RR 0. JAMA. 1999.5a (95% CI = 0.6–0.9) 20 30% 15 10 RR 0.7) 55% Without Pre-Existing Vertebral Fracture With Pre-Existing Vertebral Fracture 5 0 a Women who completed the study and had evaluable radiographs at 36 months. et al.7a (95% CI = 0.3–0.282:637-645. With permission from Ettinger B. .

weekly) Risedronate (daily.Available Bisphosphonates for Osteoporosis FDA Approved  Oral – – – Alendronate (daily. weekly. monthly) Ibandronate (daily. monthly) Ibandronate (quarterly) Zoledronic acid (annual) Pamidronate (IV quarterly)  Intravenous – –  Off-label – .

ALENDRONATE .

.6): with and without existing vertebral fracture Specifically designed to investigate the effect of alendronate on the reduction in the risk of fractures: – vertebral (symptomatic and morphometric) – any symptomatic – any non-vertebral – hip – forearm  FIT = Fracture Intervention Trial.05).85:4118–4124. 2000. J Clin Endocrinol Metab.. a Significant cumulative difference from placebo (P<0. et al.THE FRACTURE INTERVENTION TRIAL (FIT): A LANDMARK STUDY IN OSTEOPOROSIS  First comprehensive fracture study in postmenopausal women with bone mass (T < -1. Adapted from Black DM.

.030 0 0 6 12 18 Months 24 30 36 J Bone Miner Res.5 at baseline % of Patients with Fracture 3 2 59% Reduction § § 1 § P < 0. 1999 Supplement.EVIDENCE OF EARLY EFFICACY AT THE SPINE ALENDRONATE: FRACTURE INTERVENTION TRIAL COMBINED ANALYSIS1 4 Clinical (Symptomatic) Vertebral Fractures PBO (n = 1817) ALN 5/10 mg (n = 1841) § § § N = 3658 Age = 55 to 80 years Patients with preexisting VFx’s or FN BMD T-score < –2.

348.Summary of Fracture Results Type of fracture % incidence P value reduction 47 <0.001 At least one new vertebral fracture Multiple (>2) new vertebral fractures Clinical (symptomatic) vertebral fracture Lancet.FIT TRIAL .001 90 <0. 1996 .001 55 <0.

3% (P<0. Adapted from Bone HG.7% (P<0.7% (P<0. Year FOSAMAX™ (alendronate) is a trademark of Merck & Co.350:1189–1199. NJ. Whitehouse Station.. USA. Inc. .001) Total Hip 6. N Engl J Med..001) e gna h C % ES± nae M ) ( 2 0 0 1 2 3 4 5 6 7 8 9 n=86 10 n=196 n=151 n=122 BMD = bone mineral density.001) Hip Trochanter 10. et al. 2004.ALENDRONATE PROVIDED SUSTAINED IMPROVEMENT IN BMD OVER 10 YEARS 14 Alendronate10 mg daily 12 10 8 6 4 Spine 13.

 RESIDRONATE .

8 % w/ VFx at baseline = 100% • Median VFx at baseline = 34 1. Osteo Int. 2000.7 • % w/ VFx at baseline = 100% • Mean VFx at baseline = 2.11:83-91 . 1999.226 Mean Age = 71 Mean LS T-score = –2.RISEDRONATE VERTEBRAL FRACTURE STUDIES1. Harris ST. JAMA.5  INTERNATIONAL STUDY2 • • • • n = 1.2  NORTH AMERICAN STUDY1 • n = 2.282(14):1344-1352 2.458 • Mean Age = 69 • Mean FN T-score = –2. Reginster JY.

Antifracture efficacy of Risedronate over time 41% Year 3 55% Year 2 65% Year 1 0.75 1 New Morphometric Vertebral Fractures Risedronate USPI Harris ST. et al.5 0. JAMA 1999.25 0.282:1344–52 .

 IBANDRONATE .

6% = 5.6%1 1 Barrett J.5mg Bimonthly i. 2mg NOT LICENSED *ACE = annual cumulative exposure = dose x doses/year x absorption (e.5mg) Monthly oral† 150mg Quarterly IV 3mg Daily oral† 2.Meta-analysis compares dose groups defined by ACE* Higher doses (ACE 10. 2.5mg ACE) † Absorption for oral ibandronate = 0.g. et al.5 x 365 x 0. J Clin Pharmacol 2004.44:951–65 .8–12mg) compared with Lower dose (ACE 5.v.

0001 vs placebo) Fracture rate at 3 years (%) 8 6 4 2 0 Placebo Daily ibandronate Chesnut CH.19:1241–9 .10 Daily ibandronate reduces vertebral fracture risk 62% RRR (p=0. J Bone Miner Res 2004. et al.

Fast and consistent efficacy of Ibandronate over time 62% 61% 58% Year 3 Year 2 Year 1 0.5 0.75 1 Relative risk (95% CI) for new vertebral fractures .25 0.

 Zoledronic acid .

1% – All three biochemical markers of bone turnover decreased significantly as compared with the placebo group .Zoledronic acid /Horizon trial  In a 3 year trial .once yearly treatment reduced – Risk of vertebral fractures by 70% compared with placebo – Risk of hip fracture 41%compared with placebo – Bone mineral density increased by 7% at spine – -Total hip Bone density increased by about 5.

HORIZON TRIAL .

etidronate and teriparatide. 3. raloxifene. 2005.FRACTURE RISK REDUCTION BY BISPHOSPHONATES* Data not from comparative trials Relative Risk Reduction (95% CI) Fracture Type Vertebral Hip Wrist Other NonVertebral Alendronate1 44% (32 to 54%) Risedronate1 39% (25 to 50%) Ibandronate2 50% (26 to 66%) Zolendronate3 70% (62 to 77%) 38% (2 to 60%) 26% (7 to 41%) NS NS NS 41% (17 to 58%) 33% (-31 to 66%) 32% (-8 to 57%) 19% (-6 to 38%) 19% (3 to 32%) 24% (9 to 36%) 25%** (13 to 36%) NS = non-significant. ** Includes wrist and hip fracture results 1. N Engl J Med. . 2007.21(3):391–401. et al. Black DM. compared with strontium ranelate.356:1809-1822. * Data not from comparative trials. Stevenson M. et al. Chesnut CH. Sheffield: School of Health and Related Research (ScHARR)) 2. et al (2006) Analyses of the cost-effectiveness of pooled alendronate and risedronate. Curr Med Res Opin.

OSTEOPOROSIS TREATMENT IN 2009 SUMMARY • HRT: no prospective fracture data • • • • • • • SERMS: spine fx.  hip fx ≅ 50% Risedronate:  spine fx ≅ 50%.  hip fx ≅ No hip fx reduction Zolendronic :  spine fx ≅ 70.  hip fx ≅ 40% .  hip fx ≅ 30% Ibandronate:  spine fx ≅ 50%. No effect on peripheral fx Calcitonin: possible spine fx. No hip data Alendronate:  spine fx ≅ 50%. No hip data Vitamin D analogues: possible spine fx.

TERIPERITIDE .

1 % Percent change from baseline over a 19 month followup period (length of randomization) .8 % 5 .7 % 1 3.Intermittent PTH administration increased vertebral and femoral bone density Spine Hip  PTH (20 µg) PTH (40 µg) 9 .7 % 2 .

. et al.Basic Lab Tests Before Starting Teriparatide      Serum calcium Alkaline phosphatase 25 hydroxy-vitamin D PTH Serum creatinine Miller PD. 2004.10:139–148. Endocrine Practice.

Decrease in the risk of vertebral and non vertebral fractures (20 µg) PTH (40 µg) PTH One or more new vertebral fracture Non vertebral fractures 65 % 35 % 69 % 40 %   Significant risk reduction of new vertebral fractures (vs placebo) Significant risk reduction of new non vertebral fractures .

et al. N Engl J Med.Effect of Teriparatide on Risk of Vertebral Fractures in Postmenopausal Women 16 RR 0.55)a % of Patients with ≥1 Fracture 14 12 10 8 6 4 2 0 Placebo Teriparatide 20 µg 65% ↓ a P <. 2001. Neer RM.344:1434-1441.22–0.35 (95% CI = 0.001 vs placebo. Paul Miller. Graphic courtesy of Dr. .

fda. Fortical®) Raloxifene (Evista®) Ibandronate (Boniva®) Alendronate (Fosamax®) Risedronate (Actonel®) Zoledronic acid (Reclast®) Teriparatide (Forteo®) www.gov Prevention Treatment Glucocorticoid-induced Osteoporosis Prevention Treatment Men                    .FDA-APPROVED MEDICATIONS INDICATIONS Postmenopausal Osteoporosis Drug Estrogen Calcitonin (Miacalcin®.

 hip fx ≅ No hip fx reduction Zolendronic :  spine fx ≅ 65%.  hip fx ≅ 30% Ibandronate:  spine fx ≅ 50%.  hip fx ≅ 50% Risedronate:  spine fx ≅ 50%.  hip fx ≅ 40% .OSTEOPOROSIS TREATMENT IN 2009 SUMMARY • HRT: no prospective fracture data • • • • • • • SERMS: spine fx. No hip data Alendronate:  spine fx ≅ 50%. No hip data Vitamin D analogues: possible spine fx. No effect on peripheral fx Calcitonin: possible spine fx.

Indications for IV .1  Inability to take oral bisphosphonate – – – – Can’t swallow tablets Poor compliance with dosing instructions Poor adherence/persistence in general Cognitive impairment    Patient preference Perhaps in context of polypharmacy “Treatment failures” – Eg decreasing bone densities and further fractures .

daily dosing Effective . ↑MI. ↑CVA Less effect on BMD GI intolerance ? Mechanism Expensive. daily injections Bisphosphonates ↓ vert and nonvert Fx Strontium Teriparatide Bulky. accessible Effective ↓ vert Fx. ↓ breast ca Con’s Partial efficacy ↑breast ca. ↑DVT.Pro’s and Con’s of Available Osteoporosis Therapies Agent Calcium/Vit D HRT Raloxifene Pro’s Cheap.

surgeongeneral.eatright.org More information about the Surgeon General’s Report on Bone Health and Osteoporosis is available on the Surgeon General’s website at: www.michiganosteoporosisconnection.For More Information on Osteoporosis American Dietetic Association Phone: (800) 877-1600 Website: www.org National Osteoporosis Foundation Phone: (800) 223-9994 Website: www.org National Dairy Council Website: www.org Michigan Public Health Institute.Osteoporosis Program Phone: (517) 324-8363 www.org National Institutes of Health Osteoporosis and Related Bone Disease~National Resource Center Phone: (800) 624-2663 Website: www.gov Website: .nationaldairycouncil.nof.osteo.

Other Changes “Fall-proof” your home Graphic used with permission from The 2004 Surgeon General’s Report on Bone Health and Osteoporosis: What It Means To You. .

Future Treatment and Prevention of Osteoporosis and Fractures: .

New and Emerging Treatments Antiresorptive (anticatabolic)  Denosumab  Odanacatib  Lasofoxifene  Bazedoxifene  CE/bazedoxifene  New delivery systems – oral salmon calcitonin Osteo-anabolic (bone-forming)     Sclerostin inhibitor Variations of PTH Endogenous PTH stimulation – calcium sensing receptor antagonist (calcilytic) New delivery systems – transdermal PTH Strontium ranelate Combinations of antiresorptive and anabolic .

Anti Cathepsin K: Baticalib Cathepsin K is an Enzyme produced by Osteoclast. so reduced the bone formation.Denusomab: Prolia Its an anti RankL drug approved by FDA for post menopausal Osteoporosis. AntiSclerostin: Sclerostin is produced by Osteocytes of a person who has inactive lifestyle. Anti Cathepsin K is an oral drug . necessary for bone resorption. It blocks the of Wntβ / Catenin pathway. Anti sclerostin is soon available for Osteoporosis treatment.

TNFβ. TRAIL. . TRAIL. Boyle WJ.19:1059-1066. tumor necrosis factor. or CD40L Pharmacokinetics (SC): similar to other fully human IgG2 monoclonal antibodies – – – – – Absorption is rapid and prolonged (Cmx ≈1–4 wks postdose) a Long half-life ≈34 days with maximum dose Distribution ≈ intravascular volume Clearance ≈ reticuloendothelial system No kidney filtration or excretion of intact molecule Abbreviations: TNF. TNF-related apoptosis-inducing ligand. 2004. J Bone Miner Res. Nature.423:337-342. et al. 2003. et al. Bekker PJ.Denosumab (Dmab)     Fully human monoclonal antibody-IgG2 isotype High affinity and specificity for human RANK ligand Does not bind to TNFα.

23:S81.23:S81. Eastell R. muscle spasm. 2008. J Bone Miner Res. muscle cramps Safety  Safety – Cummings SR. et al. 2008.23:1923-1934.New SERMs for Postmenopausal Osteoporosis  Efficacy – – – – – Increases BMD Reduces BTMs Decreases risk of VFs and NVFs Decreases risk of ER+ breast cancer Improves signs and symptoms  of vulvovaginal atrophy Increases risk of venous thromboembolisms (VTEs). hot flushes. . Silverman SL. J Bone Miner Res. 2008. et al. and vaginal bleeding  Efficacy – – – – Increases BMD Reduces BTMs Decreases risk of VFs Increases risk of VTEs. et al. hot flushes. J Bone Miner Res.

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