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Management of Refractory cases of Osteoporosis. Dr. Atef A. Mahmoud , MD, FRCP Professor of Internal Medicine & Rheumatology Cairo Unversity. Case Study. F.M.A,84 years old Egyptian F., MRN 707962 Rheumatology OPD: (December 1977, 67yrs old)
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Management of Refractory cases of Osteoporosis Dr. Atef A. Mahmoud, MD, FRCP Professor of Internal Medicine & Rheumatology Cairo Unversity
Case Study • F.M.A,84 years old Egyptian F., MRN 707962 • Rheumatology OPD: (December 1977, 67yrs old) • LBP, Hip and Knee pain lumbar spond., OA • No H. of chronic medical diseaes, no fx. nor FH of fx. December 1998 • BMD LS T – 1.5 FN T-1.5 • Calcium 1000mg + Cholecalciferol 400 u/d
June 2000 Graves disease , started on Neomercazol 30 mg/d controlled , dose reduced • Hypertension , AF on coumadin INR 2.7 • Dyslipidaemia on Atrovastatin 10 mg/d Repeat BMD, Auguest 2000 • Lumbar sp. T -1.65 FU -3.1% FN T -1.51 FU -3.7% • Start Alendronate Sodium 10 mg/d
Repeat BMD, January 2004 • Osteopoenia , LS + 17.8% , FN + 15.8% • December 2006, still on Fosamax, no Fx. Repeat BMD in 2006 very satisfactory • Drug holiday for 2yrs. ,continue Cal. & vit. D BMD repeated in january 2008 and March 2010 almost normal
FOSAMAX/FOSAMAXaFOSAMAX/placebo As seen in FLEX, R FOSAMAX Increased Lumbar Spine BMD More Than Placebo FIT FLEX 16 16 3.7% P<0.001 14 14 12 12 10 10 BMD Change From FITBaseline, Mean %b 8 8 6 6 4 4 2 2 0 0 0 1 2 3 4 0 1 2 3 4 5 Year Year Number FOSAMAX/FOSAMAX 648 648 647 645 449c 646 595 553 FOSAMAX/placebo 431 429 430 426 293c 429 402 365 FLEX = FIT Long-term EXtension study; BMD = bone mineral density; FIT = Fracture Intervention Trial aPooled 5-mg and 10-mg groups; bError bars indicate 95% confidence interval; cMeasured in clinical fracture arm only Adapted from Black DM et al. JAMA. 2006;296:2927–2938. FOSAMAX (alendronate sodium) is a registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. R
0 Bone Turnover: Treatment Discontinuation Urine NTx (Bone resorption) Bone et al. N Engl J Med 2004; 350: 1189-1199
As seen in FLEX, R FOSAMAX Reduced the Incidence of Clinical Vertebral Fracture More Than Placebo 25 FOSAMAX/FOSAMAX* (n=662) FOSAMAX/placebo (n=437) 18.9% 19.0% 20 Relative Risk Reduction=55% 15 Fracture Incidence, % 11.3% 9.8% 10 5.3% 5 2.4% 0 Clinical Vertebral Vertebral Morphometric Nonvertebral RR=0.45 95% CI (0.24, 0.85) RR=0.86 95% CI (0.60, 1.22) RR=1.00 95% CI (0.76, 1.32) FLEX = FIT Long-term EXtension study; RR = relative risk; CI=confidence interval *Pooled 5-mg and 10-mg groups Adapted from Black DM et al. JAMA. 2006;296:2927–2938. FOSAMAX (alendronate sodium) is a registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. R
FDA Analysis: Duration of treatment , Bisphosphonates Pooled data (n=2496)BPs 6+ years, Fx. rate 9.3-10.6% BPs/PBO, Fx. rate 8.0-8.8% The FDA found no continued efficacy with long term (beyond 3-5 y) Bisphosphonate use.
Febuary 2011 Drainge of amaebic liver abscess • September 2011 felt down from standing height
Investigations • Ser.Cr. 0.9 mg/dl , normal electrolyte • Hg 12.2 Plat. 142 WBC 14.8 N. 13.5 • ESR 28 • Cal.9.2 ALP 55 25OHD 68.7 nmol/L • Normal LFT • TSH 1.75 FT4 6.2 FT3 137 (on Neomecazol 5 mg/d)
Started on Protelos 2gm/d + calcium & Vit.D on October 2011 • April 2012 felt down communatedfx. of Lt. humerus
Protelos discontinued ( 6/12) • Teriparatide (Forteo) 20 µg SC daily started
OPD April 2013 • Forteo (12/12) , no fractures, ambulatory • Calcium 500mg/d • Cholecalciferol 800 u/d • Thyroid study normal • Ser. Calcium ,Phosphorus, ALP, 25OHD normal
Important Issues to Adress • Always check for secondary cause of bone loss. • Duration of Bisphosphonate therapy • Drug holiday concept • Long term surveilance of osteoporotic patients. • Falacies in BMD interpretation • Occurrence of fragility fractures with normal BMD measurements
Bone Stiffness • Stiffness is the rigidity of an object — the extent to which it resists deformation in response to an applied force . • The complementary concept is flexibility or pliability: the more flexible an object is, the less stiff it is. • The mineral gives bone its stiffness, without sufficient mineralization, bones will plastically deform under load
Bone Toughness • Toughness : is the ability of the bone to absorb shock and is a measure of resistance to fracture • Collagen provides toughness to bone making it less brittle so that it better resists fracture. • Osteoid bone has toughness but not stiffness
Bone Mineralization Mineral = 64-66% of bone matrix weight Toughness Hypomineralization Hypermineralization Mineral Content
Dogs Treated with High Doses of Bisphosphonates 20 ** * 15 Microcrack Surface Density(m/mm2) Mean ± SEM 10 5 0 Placebo Risedronate Alendronate *P<.05 vs placebo **P<.01 vs placebo Mashiba T et al. J Bone Miner Res 15:613-620; 2000
Hypermineralization of Bones • Stiffness • Toughness • Easy Fractures ( Atypical )
Why is Difficult to Define Non-Responders • BMD changes account only partially to the anti-fracture effect of different therapies • Need to wait 1-2 years to assess BMD response • Therapies decrease but don’t eliminate fractures • Medication compliance is generally low with therapies
Potential Causes of Poor Response • The use of a weak anti-resorptive agent • Low bioavailability of the drug in the subject • Low Ca and Vitamin D intake • Underlying secondary osteoporosis • Possible low bone turnover status secondary to long term steroids use or chronic illness • Incompliance to medications
Effect of Vit D Status on Response The effect of cyclical Etidronate in women with low BMD with Vit D depleted (<40 nmol/L)or repleted (>40 nmol/L) Koster et al, Eur J Pharm, 1996,51:145
Definition of Non-responders • In the FACT study Nonresponders were defined as having any measured BMD loss (from baseline) at two or more of the four measured sites at 24 months. • Conversely Responders were defined as having either no change or any measured gain in BMD. • In this study 85% of Alendronate patients and 62% of Residronate patients were responders after 24 months.
Definition of Non-responders (EUROFOROS) 1-Sustained at least one new vertebral or nonvertebral fragility fracture despite prior prescription of an AR therapy for at least 12 moths 2-Had a lumbar spine, total hip, or femoral neck BMD T-score of -3.0 or less after documented prior AR treatment for at least 24 moths; and/or 3-Experienced a decrease of >3.5% in BMD in 2 yr at any one of the skeletal sites measured, despite documented continuous prescription of an AR agent in the preceding 24 moths.
Management of Poor Responders • The use of other anti-osteoporosis agent • Optimal intake of Ca and Vitamin D • Treatment of underlying causes of secondary osteoporosis ( 30% of PM women and 40% in osteoporotic men) • Role of other new therapies and anabolic agents ?
Thank You Dr.Atef Mahmoud
Management of Refractory cases of Osteoporosis Dr. Atef A. Mahmoud, MD, FRCP Head of Rheumatology & Rehabilitation Unit, Dr. Erfan& Bagedo Hospital
14 12 10 8 6 4 2 0 Continuous Increases in Lumbar Spine BMD with Alendronate 10 mg over 10 Years (13.7%) p<0.001 (9.3%) p<0.001 (9.3%) p<0.001 Mean Percent Change (±SE) ALN 5 mg (n=78) ALN 10 mg (n=86) ALN 20 mg/ALN 5 mg/Placebo (n=83) 0 1 2 3 4 5 6 7 8 9 10 Year The mean percent change from baseline to year 10 appears in parentheses following each treatment group. Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.
9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 8 9 10 0 Sustained Increases in Total Hip BMD with Alendronate 10 mg over 10 Years ALN 5 mg (n=78) ALN 20 mg/ALN 5 mg/Placebo (n=83) ALN 10 mg (n=86) (6.7%) p<0.001 Mean Percent Change (±SE) (3.4%) p<0.001 (2.9%) p<0.05 Year The mean percent change from baseline to year 10 appears in parentheses following each treatment group. Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.
0 Total Hip BMD Changes From FIT Baseline (mITT) ALN/Placebo ALN/ALN (Pooled 5 mg and 10 mg groups) P < 0.001 ALN/ALN vs ALN/PBO. 5 4 3 2.57% (1.78-3.36) 2 Mean Percent Change 1 0 FIT FLEX –1 0 12 24 36 48 60 72 84 96 108 120 Month Black et al JAMA 2006; 296: 2927-2938
Bone Composition: Stress & Strain Normal X OsteoPetrosis X Stress OsteoMalacia X Strain
Treating the high risk patient Osteoporosis Standard Treatment “Failure” BMD and/or Turnover Fracture High Risk Patient Anabolic Rx (PTH) Escalate Treatment