Update in Osteoporosis: Disclosures. Topics

Transcription

1 Update in Osteoporosis: 21 Michael Maricic, M.D. Catalina Pointe Rheumatogy Clinical Associate Professor of Medicine University of Arizona Disclosures Speakers Bureau, Consultant or Clinical Research Grant Support Merck Proctor and Gamble Aventis Lilly Novartis Amgen Roche Glaxo-Smith-Kline Topics Are vertebroplasty/kyphoplasty safe and effective Who should receive them Is generic alendronate as safe and effective as Fosamax? ONJ and Subtrochanteric femoral fractures with bisphosphonates Should patients on bisphosphonates for 5 years or more be given a drug holiday?

2 Topics Is it safe to use bisphosphonates or rpth with abnormal renal function? New Guidelines and Treatments for Glucocorticoidinduced osteoporosis? Where will denosumab fit into the therapeutic paradigm? Emerging therapies for osteoporosis? Are vertebroplasty/kyphoplasty safe and effective Original Article A Randomized Trial of Vertebroplasty for Painful Osteoporotic Vertebral Fractures Rachelle Buchbinder, Ph.D., Richard H. Osborne, Ph.D., Peter R. Ebeling, M.D., John D. Wark, Ph.D., Peter Mitchell, M.Med., Chris Wriedt, M.B., B.S., Stephen Graves, D. Phil., Margaret P. Staples, Ph.D., and Bridie Murphy, B.Sc. N Engl J Med Volume 361(6):5 August 6, 29

3 Scores on Measures of Overall Pain, Pain at Night and at Rest, Quality of Life Questionnaire Assessment of Quality of Life, and Disability Questionnaire Buchbinder R et al. N Engl J Med 29;361: Original Article A Randomized Trial of Vertebroplasty for Osteoporotic Spinal Fractures David F. Kallmes, M.D., Bryan A. Comstock, M.S., Patrick J. Heagerty, Ph.D., Judith A. Turner, Ph.D., David J. Wilson, F.R.C.R., Terry H. Diamond, F.R.A.C.P., Richard Edwards, F.R.C.R., Leigh A. Gray, M.S., Lydia Stout, B.S., Sara Owen, M.Sc., William Hollingworth, Ph.D., Basavaraj Ghdoke, M.D., Deborah J. Annesley-Williams, F.R.C.R., Stuart H. Ralston, F.R.C.P., and Jeffrey G. Jarvik, M.D., M.P.H. N Engl J Med Volume 361(6): August 6, 29 Secondary Outcome Measures at 1 Month (Intention-to-Treat Analyses) Kallmes DF et al. N Engl J Med 29;361:

4 Scores on Measures of Disability and Pain over a 3-Month Period Kallmes DF et al. N Engl J Med 29;361: Are vertebroplasty/kyphoplasty safe and effective Who should receive them? Which is more effective / safe? Patient selection Timing after fracture Does severity or number of fractures influence outcome? What about Generic Alendronate? Apotex, Inc. Barr Pharmaceuticals, Inc. Cobalt Laboratories, Inc. Dr. Reddy's Laboratories, Ltd. Mylan Pharmaceuticals, Inc. Barr Pharmaceuticals, Inc. Teva Pharmaceuticals Watson Laboratories, Inc.

5 Requirements for Generic Drugs To gain FDA approval, a generic drug must: Contain the same active ingredients as the innovator drug (inactive ingredients may vary) Be identical in strength, dosage, and route of administration Have the same use indications Be bioequivalent Generic Alendronate: Concerns While drugs must be bioequivalent, the FDA allows a variation of 2% of bioavailability. This is a range from 8% - 125% AUC, where there is considered to be no statistically significant difference. Fosamax vs Generic Alendronate 186 post menopausal women T score < months prior Bisphosphonate therapy Treatment 1. Brand Fosamax 7 mg/wk 2. Generic Alendronate 7 mg/wk 3. Actonel 35 mg/wk Ringe J. Rheumatol Int. 29 May 9 Ringe JD. Rheumatol Int. 29 May 9.

6 L/S Spine BMD Change Ringe J. Rheumatol Int. 29 May 9 Ringe JD. Rheumatol Int. 29 May 9. Hip BMD Change Ringe J. Rheumatol Int. 29 May 9 Ringe JD. Rheumatol Int. 29 May Month % GI Side Effects 32% 15% 9% Ringe J. Rheumatol Int. 29 May 9 Ringe JD. Rheumatol Int. 29 May 9.

7 What Should Clinicians do About Generic Alendronate? Use only in patients who are likely to be compliant with weekly bisphosphonates Consider other alternatives in high risk patients Closely monitor response with BMD or biochemical markers Is it safe to use bisphosphonates with abnormal renal function? Zoledronic Acid: Renal Safety in HORIZON-PFT

8 Zoledronic Acid: Post-Marketing Renal Safety There have been 25 cases of ARF reported to the FDA in patients given Zoledronic acid as of July 29 Zoledronic Acid is not indicated in patients with a creatinine clearance of < 35 ml/min What about Oral bisphosphonates and CKD: Risedronate Miller PD, Roux C, Boonen S, et al. J Bone Miner Res. 25;2: retrospective analysis of data from nine randomized controlled trials that included a total of 8,996 patients Severe renal impairment: CrCl <3 ml/min Moderate renal impairment: CrCL 3 5 ml/min Mild renal impairment: Creatinine clearance (CrCl) 5 8 ml/min Osteonecrosis of the Jaw A confirmed case of bisphosphonate-associated ONJ was defined as an area of exposed bone in the maxillofacial region that did not heal within 8 weeks after identification by a health care provider in a patient who was receiving or had been exposed to a bisphosphonate

9 ONJ Comparative Risks (1) Women age (from Swedish National Bureau of Statistics and database of Olmsted County, MN, USA.) M. Lewiecki 27 Kanis JA et al. Osteoporos Int. 21;12: Pharmcoepidemiol Drug Saf. 23;12: National Center for Health Statistics. JADA. 26;137: Fosamax: Is Long Term Use Linked to Subtrochanteric Femoral Fractures? ABC News Good Morning America March 9, 21 Atypical Fractures of Femoral Shaft Transverse fractures of the femoral shaft Bilateral in 2/3 of patients Delayed healing or non-healing common Prolonged use (> 5 years) of alendronate +/- other anti-resorptive medications Severely suppressed bone turnover?

10 Subtrochanteric Stress Fracture Associated with a Typical Cortical Stress Reaction Kwek E et al. N Engl J Med 28;359: Atypical Fractures of Femoral Diaphysis Visekruna, J Clin Endocrinol Metab 28;93: Copyright 28 The Endocrine Society American Academy of Orthopedic Surgery meeting: March 8, 21 One study compared the bone structure of 61 women with osteoporosis taking bisphosphonates for > 4 years to 5 patients taking calcium and vitamin D supplements. There was an association between prolonged therapy and declining cortical bone structural integrity. The second study, looked at bone samples taken from 21 post-menopausal women treated for femoral fractures. 12 patients had taken bisphosphonates (average of 8.5 yrs) - 9 hadn t been treated with the drugs. Subjects taking bisphosphonates had a reduction in bone tissue heterogeneity compared with women not receiving the drugs

11 Subtrochanteric and Diaphyseal Femur Fractures in Patients Treated With Alendronate: A Register-Based National Cohort Study Analyzed data from 11,944 patients with osteoporosis Atypical subtrochanteric femur fractures had many similar features in common with classical osteoporotic hip fractures, including patient age, gender, and trauma mechanism. The data showed that patients taking bisphosphonates and those not taking bisphosphonates had similar numbers of atypical subtrochanteric femur fractures relative to classical osteoporotic hip fractures Abrahamsen B., Eiken P., Eastell R. J Bone Miner Res. 29 Jun;24(6): Subtrochanteric and Diaphyseal Femur Fractures in Patients Treated With Alendronate: Abrahamsen B., Eiken P., Eastell R. J Bone Miner Res. 29 Jun;24(6): Subtrochanteric Fractures: Results from the HORIZON-Recurrent Fracture Trial 2127 men and women with hip fractures Compared baseline characteristics of patients with subtrochanteric femoral fractures and compared them to patients with other types of incident hip fracture Adachi J, et al ASBMR 29

12 Subtrochanteric Fractures: Results from the HORIZON-Recurrent Fracture Trial At baseline, a total of 16/2127 (5.%) patients had sustained subtrochanteric fractures The mean age, age, sex and BMI were similar between groups. Femoral neck and total hip BMD, and distribution of femoral neck BMD were similar between groups. There were no clinically relevant differences in concomitant diseases or medications (glucocorticoids, anticonvulsants or psychoactive drugs) between groups. Adachi J, et al ASBMR 29 Subtrochanteric Fractures: Results from the HORIZON-Recurrent Fracture Trial This post hoc analysis demonstrated that subtrochanteric fractures are not uncommon and do occur in bisphosphonate naive patients, though it failed to show factors that would identify those at greater risk for subtrochanteric fracture Adachi J, et al ASBMR 29 Subtrochanteric Fractures: VA Retrospective Study Reviewed 8, hip fracture classifications in VA system over past 1 years. 9% of all hip fractures were subtrochanteric No difference in incidence between those exposed or never exposed to bisphosphonates Saag et al. ASBMR 29

13 FDA Drug Safety Communication: Ongoing safety review of oral bisphosphonates and atypical subtrochanteric femur fractures March 1,21 At this point, the data that FDA has reviewed have not shown a clear connection between bisphosphonate use and a risk of atypical subtrochanteric femur fractures. FDA recommends that Patients should: Not stop taking medication unless told to do so by your healthcare professional. Talk to their healthcare professional if they develop new hip or thigh pain, or have any concerns with your medications. Report any side effects with bisphosphonates to FDA's MedWatch program FDA Drug Safety Communication: Ongoing safety review of oral bisphosphonates and atypical subtrochanteric femur fractures March 1,21 FDA recommends that Healthcare Professionals should: Be aware of the possible risk of atypical subtrochanteric femur fractures in patients taking oral bisphosphonates. Continue to follow the recommendations in the drug label when prescribing oral bisphosphonates. Discuss with patients the known benefits and potential risks with using oral bisphosphonates. Report any adverse events with the use of obisphosphonates to FDA's MedWatch program FDA Drug Safety Communication: Ongoing safety review of oral bisphosphonates and atypical subtrochanteric femur fractures March 1,21

14 Bisphosphonate Holiday? FLEX: Study Timeline FIT: 3 to 4.5 years Time Between FIT and FLEX 1 to 2 years FLEX: 5 years F F 1 F 2 F 3 F 4 FL FL 1 FL 2 FL 3 FL 4 FL 5 Year F = FIT; FL = FLEX. Ensrud KE et al. J Bone Miner Res. 24;19: Lumbar Spine BMD From Beginning of FIT to Completion of FLEX Mean Percent Change From FIT Baseline, % FIT 3 to 4.5 years Time Between FIT and FLEX 1 to 2 years FLEX 5 years 3.7% P<.1 F F 1 F 2 F 3 F 4 = ALN/placebo (n = 437) Year FL FL 1 FL 2 FL 3 FL 4 FL 5 = ALN/ALN (pooled 5-mg and 1-mg groups: n = 662) F = FIT; FL = FLEX. Black DM et al. JAMA. 26;296:

15 Total Hip BMD Change From Beginning of FIT to Completion of FLEX Mean Percent Change From FIT Baseline, % FIT 3 to 4.5 years Time Between FIT and FLEX 1 to 2 years FLEX 5 years 2.4% P<.1 1 F F 1 F 2 F 3 F 4 = ALN/placebo (n = 437) FL FL 1 FL 2 FL 3 FL 4 FL 5 Year = ALN/ALN (pooled 5-mg and 1-mg groups: n = 662) F = FIT; FL = FLEX. Black DM et al. JAMA. 26;296: Serum CTx: Mean Absolute Value Change From FIT and FLEX Baselines Mean Absolute Value, ng/ml FIT 3 to 4.5 years Time Between FIT and FLEX 1 to 2 years FLEX 5 years. F F 1 F 2 F 3 F 4 FL FL 1 FL 2 FL 3 FL 4 FL 5 = ALN/placebo (n = 97) Year = ALN/ALN (pooled 5-mg and 1-mg groups: n = 139) 56% P<.1 F = FIT; FL = FLEX; CTx = C-telopeptide of type 1 collagen. 1. Black DM et al. JAMA. 26;296: FLEX Incidence of Fractures 25 ALN/PLB (n = 437) ALN/ALN (n = 662) % Fracture Incidence ARR = 2.9% P =.13 RR =.45 CI (.2,.8) RR =.9 CI (.6, 1.2) RR = 1. CI (.8, 1.3) RR = 1. CI (.5, 2.1) 5% 2% 11% 1% 19% 19% Clinical Vertebral Vertebral Morphometric Abbreviations: ALN, alendronate; PLB, placebo. Black DM, et al. JAMA. 26;296: Nonvertebral 3% 3% Hip

16 FLEX: Study Design FIT N = 6,459 Placebo n = 3,223 Alendronate* n = 3,236 Eligible for FLEX screening N = 2,852 FIT (3 4.5 years) Post-FIT (1 2 years) Randomized in FLEX N = 1,99 FLEX (5 years) Placebo N n = 437 Alendronate 5 mg n = 329 Alendronate 1 mg n = 333 * Alendronate 5 mg/day for Years 1 2, then 1 mg/day. 1. Black DM et al. JAMA. 26;296: Pooled When to Consider a Bisphosphonate Holiday When patient never needed treatment in the first place Retrospective application of NOF guide After good BMD response to at least 5 years treatment and fracture risk no longer high No fracture, T-score >-2.5 Continue treatment in high-risk patients Previous fractures, T-score -2.5 and below When to End a Bisphosphonate Holiday Not clear Possible approaches Arbitrarily restart treatment after 1 2 years Monitor BMD/BTM every 6 12 months and restart treatment when significant decrease in BMD or increase in BTM Reconsider treatment plan if fracture or change in clinical status

17 New FDA-approvals for Glucocorticoidinduced Osteoporosis Alendronate Risedronate Zoledronic Acid Teriparatide Zoledronic Acid in GIOP Prevention Subpopulation Risedronate Zoledronic acid Lumbar Spine 1 Femoral Neck 1 Total Hip 2 % Change From Baseline * * 6 12 Time (months) * 6 12 Time (months) * * 6 12 Time (months) Graphs present least squares means and 95% confidence intervals. *P <.5, between treatment comparisons; P <.1, between treatment comparisons. 1. Reid DM, et al. Lancet. 29 Zoledronic acid in GIOP Treatment Subpopulation Risedronate Zoledronic acid Lumbar Spine 1 Femoral Neck 1 Total Hip 2 % Change From Baseline * * 6 12 Time (months) * 6 12 Time (months) * * 6 12 Time (months) Graphs present least squares means and 95% confidence intervals. *P <.5, between treatment comparisons. 1. Reid DM, et al. Lancet. 29

18 Teriparatide Versus Alendronate for Treatment of Glucocorticoid-induced Osteoporosis: 36-month Results KG Saag 1, JR Zanchetta 2, JP Devogelaer 3, R Adler 4,K See 5,GP Dalsky 5, K Krohn 5, JH Krege 5, MR Warner 5 Arthritis and Rheumatism 29 Study Design Screening Phase 18-month Primary Phase 18-month Continuation Phase All Subjects Teriparatide 2 μg/day + oral placebo Alendronate 1 mg/day + placebo injection Teriparatide 2 μg/day + oral placebo Alendronate 1 mg/day + placebo injection Calcium and vitamin D Calcium and vitamin D Visit -1.5 to Mont mo mo 24 mo 3 mo 36 mo h mo mo Randomizatio n End of End of Baseline Assessments Primary Phase Continuation Phase Saag et al. Arthritis and Rheumatism 29 Percent Change in BMD Mean ± SE Lumbar Spine BMD * 8.% 3.8% Teriparatide Endpoint Months Alendronate n= Teriparatide n= % 5.2% Alendronate 11.% 5.3% 8.9% 4.2% * P<.5; P<.1 Teriparatide vs. Alendronate BMD = bone mineral density, g/cm 2

19 Proximal Femur BMD Percent Change in BMD Mean ± SE 1 Femoral neck Percent Change in BMD Mean + SE 1 Total hip Teriparatide 8 8 Teriparatide 6 6 * 6.3% 5.1% % 4.4% * 2 3.4% 2.6% 2 2.7% 2.2% Alendronate Alendronate 36 Endpoint 36 Endpoint Months Months 145 ALN n= ALN n= TPTD n= TPTD n= Saag et al. Arthritis and Rheumatism 29 *P<.5, P<.1, P<.1 Teriparatide vs. Alendronate Number of Patients With New Vertebral Fractures Alendronate (n=169)* Teriparatide (n=173)* P-value Vertebral radiographic 13 (7.7%) 3 (1.7%).7 Clinical vertebral** 4 (2.4%).37 Mild 7 (4.1%) 1 (.6%).26 Moderate Severe 2 (1.2%) 4 (2.4%) 2 (1.2%) Saag et al. Arthritis and Rheumatism American College of Rheumatology Guidelines for Glucocorticoid-induced Osteoporosis Will include Zoledronic Acid as well as Teriparatide as treatment options Will incorporate Clinical Risks for Fracture as well as T-scores (similar to FRAX) to stratify low versus high risk patients

20 RANK-RANKL-OPG Pathway OPG RANKL RANK Denosumab Growth factors Hormones Cytokines RANKL OPG CFU-M Prefusion osteoclast Multinucleated osteoclast Osteoclast Stromal cells Osteoblast BONE Adapted from Boyle et al. Nature. 23;423:337. CFU-M = colony-forming unit macrophage. Denosumab for Postmenopausal Osteoporosis: FREEDOM Study BMD Lumbar spine 9.2% (P <.1) Total hip 6.% (P <.1) BTMs CTX 72% (P <.1) Fracture risk Vertebral 68% (P <.1) Hip 4% ( P =.36) Nonvertebral 2% ( P =.11) Cummings SR, et al. N Engl J Med. 29;361: FREEDOM trial: Adverse Events Adverse Events Denosumab Placebo All 92.8% 93.1% Infections 52.9% 54.4% Cancer 4.8% 4.3% Hypocalcemia %.1% ONJ % % Cummings SR, et al. N Engl J Med. 29;361:

21 FREEDOM Trial: Serious Adverse Events SAEs Denosumab Placebo All 25.8% 25.1% Infections 4.1% 3.4% Cancer 3.7% 3.2% Atrial fibrillation.7%.7% Deaths 1.8% 2.3% Cardiovascular events 4.8% 4.6% Abbreviation: SAEs, serious adverse events. With permission from Cummings SR, et al. N Engl J Med. 29;361: Emerging Therapies Antiresorptive (anti-catabolic) Denosumab Lasofoxifene Bazedoxifene CE/bazedoxifene Odanacatib New delivery systems Osteo-anabolic (bone-forming) Sclerostin inhibitor Variations of parathyroid hormone Calcium-sensing receptor antagonist (calcilytic) New delivery systems Combinations of antiresorptive and anabolic Resorbing Osteoclast

22 Signals Determining Differentiation Toward Osteoblasts and Acting on Mature Osteoblasts to Enhance Bone Formation Preosteoblast Wnt and BMP PTH Osteoblast Under the influence of Wnt and BMP, undifferentiated mesenchymal cells differentiate toward cells of the osteoblast lineage. Bone Formation New Bone Abbreviations: BMP, bone morphogenic protein; PTH, parathyroid hormone. Wnt Antagonists LRP5 and LRP6 Sclerostin DKK-1 Cell Membrane Kremen Frizzled Wnt sfrp-1 Axin APC GSK3ß ß-Catenin Proteosome Cytoplasm Nucleus The extracellular Wnt antagonists prevent Wnt signaling. Dikkopf-1 (Dkk-1) in association with Kremen and sclerostin bind LRP5 and LRP6.