Conquering Challenges in Osteoporosis Management & Treatment
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This document discusses a presentation on conquering challenges in osteoporosis management and treatment. The presentation was given by Dr. Kerstin Gustafson and disclosed relationships with various pharmaceutical companies. The objectives of the presentation were to effectively identify patients at high risk for fracture, implement osteoporosis management plans using evidence-based medicine, overcome challenges in management, and answer questions. The agenda covered the burden of osteoporosis, identifying high-risk patients, optimizing treatment, managing patients on treatment, and a question period.
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Conquering Challenges in Osteoporosis Management & Treatment
- 1. Conquering Challenges in Osteoporosis Management & Treatment Dr. Kerstin Gustafson, MDM, FRCSC, NCMP 1
- 2. Faculty/Presenter Disclosure » Faculty: Dr. Kerstin Gustafson, MDM, FRCSC, NCMP » Relationships with commercial interests: » Speaker fees: – – – – – – » Amgen Bayer Merck Novartis Novo-Nordisk Warner-Chilcott Advisory Boards – – – Lilly Amgen Novartis 3
- 3. Disclosure of Commercial Support » This program has received financial support from Amgen Canada in the form of an educational grant » This program has received in-kind support from Amgen Canada in the form of material production and logistical support » Potential for conflict(s) of interest: – Dr. K. Gustafson has received an honoraria funding from Amgen AND/OR Merck, Warner Chilcott, Eli Lilly, Novartis, whose product(s) are being discussed in this program] – Amgen developed and distributes denosumab ® a product that will be discussed in this program: denosumab (Prolia) 4
- 4. Mitigating Potential Bias » Bias has be mitigated by the following: – All program content was developed and peer-reviewed by an independent physicians steering group – All clinical recommendations are based on clinical guidelines and peer-reviewed evidence – The program has been to developed to improve PMO patient outcomes by increased screening and appropriate monitoring of patients at risk for fracture based on national needs assessment criteria – Industry has not been involved in the development of the program 5
- 5. Audience Question » Do you feel confident assessing fracture risk in women with post-menopausal osteoporosis (PMO)? A. Very confident B. Confident C. Somewhat Confident D. Not Confident 6
- 6. Learning Objectives Upon completion of this session, participants will be able to implement strategies and action steps to: Effectively identify patients at high risk for fracture Implement PMO management plans Use evidenced based medicine to optimize treatment for patients with PMO Overcome challenges in PMO management 7
- 7. Agenda Burden of Osteoporosis 5 minutes Identifying Patients at High Risk for Fracture 10 minutes Optimizing Treatment for PMO Patients 20 minutes Challenges in Managing Patients on Treatment 15 minutes Clinical Pearls & Question & Answer 10 minutes 8
- 8. Audience Question » Which of the following is most common in women over 50 years of age in Canada? A. Heart Attack B. Breast Cancer C. Stroke D. Osteoporotic Fracture 9
- 10. Prevalence of Fractures in Canada » Fractures from osteoporosis in Canadian women are more common than heart attack, stroke and breast cancer combined1 Annual incidence of common diseases 200,000 153,400 150,000 80,000 40,000 41,500 Other 38,900 Vertebral 32,700 Wrist 49,220 29,874 30,000 Hip* 0 22,700 10,300 Pelvis Osteoporotic Heart fractures1,2 Attack3 Stroke3 Breast Cancer4 *Canadian †Other hip fractures from (1); Non-hip fracture data extrapolated from (2). represents non-osteoporotic fractures sites (humerus, clavicle, hands/fingers, patella, tibia, fibula). 2 1. Leslie WD, et al. Osteoporos Int . 2010; 21:1317‐1322; 2. Burge J, et al. J Bone Miner Res. 2007;22:465-475; 3. Canadian Institute for Health Information (2009) Health Indicators. ; 4. Canadian Cancer Society. 2009. 11
- 11. Why is this Important to Family Physicians? Osteoporosis is managed primarily by Family Practice in Canada • Based on Canadian prescriptions of osteoporosis therapies Source: IMSB, Compuscript (Aug’11) 12
- 12. Only 15% of Patients are Treated After an Osteoporotic Fracture Percentage of patients (%) A fracture is to osteoporosis what a heart attack is to cardiovascular disease 100% How do we shift this paradigm? 80% 60% 80% 40% 20% 15% 0% Osteoporosis Treatment Post Fracture1 Beta Blockers Post Heart Attack2 A history of fracture is the strongest predictor of new fractures, yet post-fracture treatment rates remain low 1. Bessette L, et al. Osteoporos Int. 2008;19:79-86. 2. Austin PC, et al. CMAJ. 2008;179:895-900. 13
- 13. What are the Consequences of Underdiagnosing and Undertreating Osteoporosis? In women with hip fracture: Fracture begets future fracture Deteriorated quality of life 40% had 40% need prior fracture1 assistance walking2 Long-term care admission 18% enter LTC3 Mortality 23% die within 1 year4 • Lifetime risk of hip fracture in women >50 is 12.1%5 1. Hajcsar EE, et al. CMAJ 2000, 163:819-822.; 2. Cooper C. Am J Med. 1997:103:12S-19S; 3. Jean et al . JBMR 2013; 28:360-71. 4. Ioannidis G, et al. CMAJ 2009;181: 265-271. 5. Hopkins et al .Osteo Intl 2012; 23:921-927 14
- 14. Identifying Patients at High Risk for Fracture 15
- 15. Learning Objective Effectively identify patients at high risk for fracture. 16
- 16. Audience Question » Is a BMD T-score of -2.5 alone sufficient to diagnose osteoporosis? A. Yes B. No » Is a BMD T-score of -2.5 alone sufficient to treat osteoporosis? A. Yes B. No 17
- 17. Understanding Fragility Fracture: Key to Appropriate Patient Management BMD vs. Osteoporotic Fracture Rates/Number Fracture Rate Fracture rate per 1000 person-years 400 No of Fractures 50 450 350 300 40 30 60% of women with fragility fractures have non-osteoporotic bone mineral density (T-score >-2.5) 250 200 150 20 No of Fractures BMD distribution 60 100 10 50 0 >1.0 0.5 to 0.0 1.0 to 0.5 –0.5 to –1.0 0.0 to –0.5 –1.5 to –2.0 –1.0 to –1.5 –2.5 to –3.0 –2.0 to –2.5 < –3.5 0 –3.0 to –3.5 BMD T-scores Adapted from Siris ES, et al: JAMA 2001; 286:2815-22. 18
- 18. When Screening Remember... It's Less than 2 minutes that Pay Off! Question : “Since the last visit..." – " Have you broken any bones? " – " Have you fallen? " – " Have you had prolonged and unusual back pain? " – " Have you received oral or intravenous steroids (cortisone) " Look - Is there kyphosis? - Ability to perform the “Get up and Go” Test Measure the patient’s height EMR reminder tools may help to prompt screening4 1. Siminoski K et al. Osteoporos Int. 2006;17:290-6. 2. Papaioannou A, et al CMAJ 2010. 3. Timed Up-and-go test. Available at: http://www.saskatoonhealthregion.ca/pdf/03_Timed%20Up%20and%20Go%20procedure.pdf. 4. Loo TS et al. Arch Intern Med 19
- 19. Screening for Osteoporosis: When to do a BMD1 Aged ≥ 65 years Aged 50-64 years Aged <50 years One or more risk factors for fracture: 2°causes of osteoporosis (i.e. malabsorption) o o o Everyone Prior fragility fracture o o o o Fragility fracture after age 40 Parental hip fracture Vertebral fracture or osteopenia identified on radiography Medication with high risk of bone loss (i.e. steroids) Smoking, alcohol (≥3/d) Disorders associated with osteoporosis (i.e. RA) Low weight or major weight loss Medication with high risk of bone loss Clinical Note: If you are ordering unrelated imaging (e.g. chest x-ray) for your patient, consider adding “rule out vertebral fracture” on the order2. 1. Papaioannou A, et al CMAJ 2010;182:1864-1873. 2. Steering Group Communications Feb 9th 2012. 20
- 20. There are Two Tools Available for Fracture Risk Assessment These tools incorporate other clinical risk factors for fracture in addition to BMD 1. OC Guidelines tool available at: http://www.osteoporosis.ca/multimedia/FractureRiskTool/index.html#/Home 2. FRAX® tool available at: http://www.shef.ac.uk/FRAX/tool.jsp 3. National Osteoporosis Foundation guidelines: www.nof.org/professionals/NOF_Clinicians_Guide.pdf 21
- 21. Calculating 10-Year Absolute Fracture Risk for Postmenopausal Women: CAROC 10-year absolute fracture risk in treatment naïve women combining femoral neck T-score and age1 Increases to the next risk category 0.0 Prior fragility fracture after age 40 Prolonged corticosteroid therapy* Femoral Neck T-score -0.5 -1.0 Low Risk -1.5 < 10% -2.0 -2.5 Moderate Risk -3.0 10%–20% -3.5 Prior hip or vertebral fracture, or >1 nonvertebral fragility fracture High Risk >20% -4.0 50 55 60 65 70 75 80 85 Age (years) Lumbar spine or total hip T-score ≤ -2.5: consider the individual to be at least at moderate risk Calibrated using Canadian fracture data and have been directly validated in Canadians 2 *At least three months cumulative use during the preceding year at a prednisone-equivalent dose ≥ 7.5 mg daily 1. Papaioannou A, et al. CMAJ. 2010;182:1864-1873. 2. Leslie WD, et al. J Bone Miner Res. 2009;24:353-360. 22
- 22. Understanding a Fragility Fracture is Critical Definition of a fragility fracture*: A fracture that occurs spontaneously or following a minor trauma such as: – Fall from a standing height (ie, on the ice) – Fall from a sitting position – Fall from a supine position (bed or reclining deck chair < 1 meter high) – Fall after having missed 1 to 3 steps in a staircase – After a movement outside of the typical plane of motion or coughing * Fragility fracture includes all bones, except: skull and face, patella, hands and feet, cervical spine 1. 2. Bessette L, et al. Contemp Clin Trials 2008; 29:194-210. Brown JP, et al. J Bone Miner Res 2007;23(suppl 1): M350. 23
- 23. Medications known to cause/accelerate bone loss Medications that increase fall risk and potential to fracture • Proton Pump Inhibitors (PPI) • Selective serotonin reuptake inhibitors (SSRIs) • Aromatase inhibitors • Hormonal/endocrine therapies - (GnRH, agonists, LHRH analogs) » » » » » » » * Note: not an exhaustive list Benzodiazepines Neuroleptics Anticholinergics Anticonvulsants Antidepressants Antihypertensives Beta-blockers, nitrates, vasodilators 24
- 24. Optimizing Treatment for PMO Patients 25
- 25. Learning Objectives Implement PMO management plans. Use evidenced based medicine to optimize treatment for patients with PMO. 26
- 26. Treatment Guidelines: The Challenge of the Moderate Risk Patient Low risk (<10%) Moderate risk High risk (>20%) Papaioannou A, et al. CMAJ. 2010;182:1864-1873. Lifestyle Modification ? Lifestyle Treat Treat 27
- 27. Top 5 Reasons to Consider Treatment in the Moderate Risk Patient: 1. Fracture: vertebral (on lateral spine X-ray) or wrist fracture (in patient >65 or BMD ≤ -2.5) 2. Lumbar spine T-score << femoral neck T-score 3. Concurrent high risk disorder or medications, including: • • • • • • Hypogonadism or premature menopause (age <45 yr) Primary hyperparathyroidism Hyperthyroidism Rheumatoid arthritis Glucocorticoids (long-term or repeated use) Aromatase inhibitor therapy 4. Falls (≥2 in the past year) 5. Patient preference to be treated Steering Group Communications. Feb 9th, 2012. Based on Osteoporosis Canada Guidelines: Papaioannou A, et al. CMAJ. 2010;182:1864-1873. 28
- 28. Audience Question: » Do your elderly patients perceive osteoporosis to be as severe as heart disease, breast or colon cancer? » Is osteoporosis of major concern to them for their overall health? 29
- 29. Fracture Prevention: Importance to Your Patients » Women with a wrist fracture have double the risk of any future osteoporotic fracture1 » Vertebral fracture predicts future hip fracture2 » A hip fracture increases the likelihood of death by 3 fold3 and increases admissions to long term care4 » Vertebral fractures can cause severe, disabling back pain, dowager’s hump5, and increase the likelihood of death within 5 years (~4 times)6 » Therapy could reduce the risk of this happening7 1. Barrett-Connor E et al. Osteoporos Int. 2008;19:607-613. 2. Melton LJ III et al. Osteoporos Int. 1999; 10:214-221. 3. Ioannidis G, et al. CMAJ. 2009;181:265-71. 4. Osteoporosis Long-term Care. http://osteoporosislongtermcare.ca/ Accessed Feb 2012. 5. Watts NB. Neurosurg Focus. 2001;10(4):E12. 6. Ioannidis G, et al. CMAJ. 2009;181:265-71. 7. Siris ES, et al. Mayo Clin Proc. 2006;81:1013-1022. 30
- 30. Audience Question: » When selecting a treatment option for your patient what is of most importance to you? – Safety? – Efficacy? – Adherence? » What is of most importance to your patients? – – – – Safety? Efficacy? Preference? Cost/coverage ? 31
- 31. Evaluating Treatment Recommendations Goal of Osteoporosis Treatment: To reduce fractures through risk reduction, early diagnosis & appropriate treatment.1 Considerations: » Mechanism of action » Efficacy » Risk/benefit ratio – safety & tolerability » Generic vs. branded medication » Patient preference and adherence » Drug cost and coverage 1. Osteoporosis Canada 2008 National Report Card 32
- 32. Mechanism of Action of Available Osteoporosis Therapies Osteoclast Precursors Estrogen therapy Selective estrogen receptor modulators Hormones RANKL RANK Multinucleated Osteoclast Bisphosphonates Binds to bone; inhibits osteoclasts Teriparatide Denosumab PTH analog RANK Ligand inhibitor Osteoblast Adapted from: Boyle WJ et al. Nature 2003; 423:337-342. Osteoclast 33
- 33. Anti-fracture Efficacy of Current Therapies: Osteoporosis Canada Guidelines1 Therapeutic Options for Fracture Prevention in PMO Women1*† Bone Formation Therapy Antiresorptive Therapy Type of Fracture Bisphosphonates Alendronate Risedronate Zoledronic Acid Denosumab Raloxifene Estrogen‡ (Hormone Therapy) Vertebral Hip - - Nonvertebral∆ - Teriparatide * Based on GRADE A evidence as assessed in the Osteoporosis Canada 2010 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada † For postmenopausal women, indicates first line therapies and Grade A recommendation. ‡ Hormone therapy (estrogen) can be used as first-line therapy in women with menopausal symptoms. ∆ In Clinical trials, non-vertebral fractures are a composite endpoint including hip, femur, pelvis, tibia, humerus, radius, and clavicle. 1. Papaioannou A, et al. CMAJ. 2010;182:1864-1873. 34
- 34. BMD Efficacy of Long-term Treatment* In long term trials, BMD continues to increase or remains stable Pivotal Study Extended Treatment Duration (yrs) # of Participants % Change Lumbar Spine BMD Ŧ % Change Total Hip BMDŦ Risedronate1 VERT-MN 7 68 11.5 3.9 Alendronate¥2 FLEX 10 86 13.7 6.7 Zoledronic Acid3 HORIZON (interim analysis of 9 year study) 6 616 12.1 4.3 Denosumab4 FREEDOM (interim analysis of 10 year study) 8 2343 18.4 8.3 Medication * Not head to head analyses: Results cannot be compared due to differing study populations and methodologies. Ŧ Represents % change from BL of Pivotal Trial. ¥Represents 10 mg dose only. 1. Mellstrom D et al. Calcif Tissue Int 2004;75:462–468 2. Bone HG et al. N Engl J Med 2004;350:1189-99. 3. Black DM, et al. J Bone Miner Res. 2012; 27(2):243-254. 4. Papapoulos, S. ASBMR 2013, Abstract LB-MO26 35
- 35. What is the safety of long-term treatment? Placebo (Years 13) (n = 3861) Zoledronic Acid (Years 1-3) (n = 3875) Zoledronic Acid (Years 3-6) (n =613) Serious AEs 30.1% 29.2% 31.2% Increase in serum creatine >0.5 mg/dL 0.4% 1.2%* 2.9%* Atrial Fibrillation (Serious AE) 0.5% 1.3%* 2.0% Zoledronic Acid (HORIZON ext)2,3 – 6 years Risedronate (VERT MN ext)1 – 5 years RIS (n = 135) Placebo (n = 130) Any serious AE 24.4% 30.0% Alendronate (FLEX ext)4,5 – Years 8-10 Incidence of AEs, % Denosumab (FREEDOM Ext)6,7 Exposure-adjusted subject incidences of AEs (Rates per 100 subject-years) Discontinuatio n (n=83) 21.7 20.9 Placebo ALN (10 mg) (n=86) Serious AEs Denosumab Years 1-3 (n = 3883) Serious AEs Infections** Years 1-3 (n = 3879) Years 4-8 (n = 2343) 10.4 10.6 10.7 1.3 1.5 1.4 • ONJ and atypical femoral fractures have been reported • **Incidence of celllulitis/erysipelas similar in extension to that seen in placebo group of pivotal trial * p<0.05 compared to placebo 1. Sorensen OH, et al. Bone 2003;32:120-126. 2. Black D, et al. N Eng J Med. 2007; 356 : 1809-1822. 3. Black DM, et al. J Bone Miner Res. 2012; 27(2):243-254. 4. Black DM JAMA. 2006; 296: 2927-38. 5. Bone HG et al. N Engl J Med 2004;350:1189-99. 6. Papapoulos S et al. J Bone Miner Res. 2012;27:694-701. 7. Papapoulos, S. ASBMR 2013, Abstract LB-MO26 36
- 36. Safety and Tolerability of Available Treatments Bisphosphonates Denosumab Raloxifene Teriparatide Hypocalcemia* Hypocalcemia* Vasodilation Transient orthostatic hypotension GI symptoms† Infections (serious events 4.1% vs. 3.4% placebo) Venous thromboembolism (↑ risk vs. placebo) Osteosarcoma (only observed in animal trials, not clinical trials) Postmarketing reports of musculoskeletal pain Dermal events (10.8% vs. 8.2% placebo) Lipid and triglyceride monitoring Urolithiasis § Osteonecrosis of jaw‡ Osteonecrosis of jaw‡ Stroke¶ Atypical Fracture (rare) Atypical Fracture (rare) Renal impairment ** Suppression of bone turnover Atrial fibrillation (2.5% vs. 1.9% placebo) * Correct with adequate calcium & Vitamin D intake prior to initiating therapy. † Rarely, oral bisphosphonates have been associated with severe esophageal events. ‡ Uncommon; mostly with cancer patients and/or dental procedures. ¶ Consider risk/benefit balance for women with a history of stroke or risk factors for stroke or venous 37 thromoboembolism.§Urinary calcium monitoring should be considered for patients with active urolithiasis and hypercalciuria. ** Recommended that all patients have their renal function assessed prior to treatment. Refer to respective Product Monographs for full Prescribing Information.
- 37. Is your patient afraid to take their medication? Help put patient concerns in perspective Fatal motor vehicle accidents 8.4/100,000 person/year1 Murder ONJ* 1.8/100,000 person/year2 <1/100,000 pts/year3 Atypical fracture** 2/100,000 pts on 2 yrs BPs 113.3/100,000 pts on 8 yrs BPs4 For every 100 hip fractures prevented there is 1 atypical femur fracture5 *The risk of ONJ is higher among cancer patients treated with high doses anti-resorptives6 **Reports of AFF have also been documented with other osteoporosis therapies7-8 and in patients who have never received BP therapy9 1. Transportation Canada. 2007 Casualty Rates. http://www.tc.gc.ca/eng/roadsafety/tp-tp3322-2007-1039.htm#t5. 2. Statistics Canada. 2009 Homicide Rate. http://www40.statcan.ca/l01/cst01/Legal12b-eng.htm. 3. Khan A, et al.J Rheumatol. 2011;38:1396-1402. 4. Dell R, et al. JBMR 2011. 27(12): 2544-2550. 5. Wang et al JBMR 2011; 26: 553- 38
- 38. How do I Approach Drug Holiday in Osteoporosis Management? Drug holiday: time off of bisphosphonate therapy, assuming reinitiation in future1. RECOMMENDATIONS: Patients at HIGH RISK for fracture should continue therapy2 After 3-5 years of therapy, re-assess your patient1,3-4: BMD ≤ -2.5 or fracture or ongoing glucocorticoid therapy Evaluate Continued Therapy BMD >-2.5 and no fracture Consider A Drug Holiday 1. Watts NB & Diab DL. J Clin Endocrinol Met; 2010, 95 (4): 1555-1565 2. Papaioannou A, et al. CMAJ. 2010;182:1864-1873. 3. Black DM et al. NEJM 2012;366:2051-2053. 4. Cummings SR et al. JBMR 2013; 28: 439-441 39
- 39. Challenges in Managing Patients on Treatment 40
- 40. Learning Objective Overcome challenges in PMO management. 41
- 41. Audience Question: » If your currently treated patient is not responding to treatment (decrease in BMD) on an oral bisphosphonate, what would you recommend? A. A different oral bisphosphonate (alendronate/risedronate) B. A medication with a different mechanism of action (i.e. denosumab, raloxifene) C. A medication with a different route of administration (i.e. denosumab, zoledronic acid) D. Continue to monitor her (no change in therapy) 42
- 42. Ensure that a Loss in BMD is not due to Secondary Causes of Osteoporosis What are the recommended Biochemical Tests? » Calcium, corrected for albumin » Complete blood count » Serum creatinine (eGFR) » Alkaline phosphatase » Thyroid stimulating hormone (TSH) » Serum protein electrophoresis for patients with vertebral fractures » 25-hydroxy vitamin D (25-OH-D)* * Should be measured after 3-4 months of adequate supplementation and should not be repeated if an optimal level ≥75 nmol/L is achieved. 1. Papaioannou A, et al. CMAJ. 2010;182:1864-1873. 43
- 43. Is your patient failing on treatment? Treatment failure can be considered after 1 year on therapy if1: - Patient has a decrease in BMD on treatment (4-5%) - Patient has 2 or more fragility fractures on treatment » Are there any new risk multipliers in your patient’s profile that would increase bone loss? – Change in medications – Co-morbidities » Consider that lack of adherence could also cause treatment failure 1. Diez-Perez A et al. Osteoporos Int 2012 23:2769-2774 44
- 44. Is your patient taking their oral BP properly? Instructions for taking oral BPs: In the morning, at least 1/2 hour before breakfast Should remain sitting upright for at least 1 hour Take only with water* Take alone, with no other medications Give only to residents who can swallow effectively Vitamin D and calcium supplements should be taken at a different time *Risedronate DR – needs to be taken with food www.osteoporosislongtermcare.ca 45
- 45. Consider Drug Intolerance » Generic agents may not be as well tolerated as the branded version1 » Risedronate DR – may ease administration burden, however, in the clinical trial the GI events were similar to those seen with Actonel weekly2 – Calcium supplements must be given separately 3 » For patients with osteoporosis using PPIs: – Ensure optimal calcium and vitamin D supplementation and instruct patient to optimize food intake of calcium – Prescribe the lowest effective PPI dose and review indication and alternatives periodically – Consider alternate formulation of calcium (eg, calcium citrate) 1. Papaioannou A, et al. J Clin Densitometry 2008;11:458-459. Abstract 152. 2. McClung MR et al. Osteoporos Int 2012:; 23: 267-276 3. Actonel Product Monograph, Warner-Chilcoott. 46
- 46. Polypharmacy: An Adherence Issue in Osteoporosis Patients » Patients on osteoporosis medication have a high likelihood of being on multiple medications for other chronic diseases – 40% of women on bisphosphonate therapy are also on ≥4 other concomitant medications1 » Polypharmacy can decrease adherence rates – Women on several other medications were 21% more likely to discontinue weekly BPs2 BP = bisphosphonate 1. Gold DT, et al. Gend Med. 2008;5:374-84. 2. Lo JC, et al. Osteoporos Int. 2006;17:922-928. 47
- 47. Would Switching Therapy Benefit Your Patient? After switching from alendronate, denosumab increases BMD1 and zoledronic acid maintains2 BMD at lumbar spine Percent Change in Lumbar Spine BMD (%) Zoledronic acid 5 mg QY (n = 113) Alendronate 70 mg QW (n = 241) Alendronate 70 mg QW (n = 112) 3.03% 3 † 2 1.85% 1 P<0.0001 0 0 6 Study Month 12 Percentage Change In Lumbar Spine BMD (%,) Denosumab 60 mg Q6M (n = 246) 4 4 3 2 1 0.81% NS 0.17% 0 0 12 Study Month n = number of patients. NS = not statistically significant » No increase in adverse events upon switching therapies1,2 Adapted from: 1. Kendler DL, et al. J Bone Miner Res. 2010;25:72-81. 2. McClung M, et al. Bone. 2007;41:122-128. 48
- 48. Would Switching Therapy Benefit Your Patient? Greater increases in BMD at 12 months in patients who transitioned to denosumab vs. patients who transitioned to risedronate1 Patients were previously on alendronate but had stopped taking alendronate or had insufficient adherence. BMD data results are not meant to imply fracture efficacy and should not be extrapolated to predict differences in fracture efficacy. Head-to-head fracture studies have not been conducted. *Data are least-squares means and 95% confidence intervals. †p < 0.0001 denosumab vs risedronate. 1. Roux C, et al. Bone 2014; 58: 48-54. 49
- 49. When Selecting a Therapy Consider That Adherence is Different Between Treatments Open-label, randomized, cross-over study of denosumab subcutaneous 60 mg Q6M and oral alendronate 70 mg QW Year 1 Denosumab (N = 126) Alendronate (N = 124) Proportion of Subjects Adhering Year 2 Treatment cross-over 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 Denosumab (N = 106) Alendronate (N = 115) 0.6 0.5 126 124 124 111 124 107 118 97 118 95 DMAb ALN 0 12 24 36 48 60 Study Week For each treatment group, time points with > 95% cumulated subjects were excluded Freemantle N, et al. Osteoporos Int 2012;23(1):317-26. 0.5 106 115 106 93 106 87 104 82 104 77 DMAb ALN 0 12 24 36 48 60 Study Week 50
- 50. Patient Support Programs can Improve Adherence Consider patient support programs offering services such as nurse support, reimbursement information, dose reminders, and education1,2 Adherence in these programs has been shown to be as high as 94%3 Reputable websites on osteoporosis and therapies may also provide patients with valuable information • Osteoporosis Canada4: • Patient and physician resources • Links to scientific references • HealthandBone.ca5: • Educational website for patients • Drugcoverage.ca6: • Search tool • Overview of private insurance plans and government drug benefit programs 1. For My Bones Program. Available at: https://www.formybones.ca/help_en.do. Accessed October 2010 report 2. Patient Direct, ProVital ™ Program. Available at: http://www.provital.ca. Accessed Nov 30, 2011. 3. Patient Direct, ProVital ™ Program, as at Nov 30, 2011 report. 4. Osteoporosis Canada. Available at: http://www.osteoporosis.ca. Accessed November 2010. 5. Health and Bone. 51 Available at: http://www.healthandbone.ca/en/home. Accessed November 2010. 6. Drug Coverage.ca Available at: http://www.drugcoverage.ca Accessed October 2010.
- 52. Clinical Pearls for Patient Assessment: 1.Have they fallen? 2.Has their BMD decreased (>3%) since their last BMD? 3.Have they lost height? (> 2cm height since last visit or >6 cm historically) 4.Have they broken any bones? 5.Are there any other risk factor multipliers to consider? –If yes: they are at increased fracture risk and should be further assessed, possibly by a lateral x-ray 53
- 53. Clinical Pearls for Who to Treat » Treat all patients at HIGH RISK for fracture: –Prior hip or vertebral fracture –Multiple fractures –10 yr absolute fracture risk >20% » Patient at MODERATE RISK for fracture: – Consider additional risk factors – Discuss fracture risk and treatment options with patient 54
- 54. Clinical Pearls for Patient Management 1. Individuals at HIGH RISK for fracture should continue osteoporosis therapy without a drug holiday1 2. Discuss benefit vs. risk of therapy with patients 3. When monitoring patients on therapy, consider: • Long-term efficacy • Safety & tolerability • Adherence • Patient preference 1. Papaioannou A, et al. CMAJ. 2010;182:1864-1873. 55
- 55. Final Clinical Pearl • The goal of PMO treatment and management is preventing a fracture. Healthy bones are strong bones! 56
Hinweis der Redaktion
- This slide must be visually presented to the audience AND verbalized by the speaker.
- This slide must be visually presented to the audience AND verbalized by the speaker.
- This slide must be visually presented to the audience AND verbalized by the speaker.
- Speaker notes:Poll participants on their response to the questionResults will be posted on the screenNo correct answer
- Speaker notes:Poll participants on their response to the questionResults will be posted on the screenThe correct answer is D Osteoporotic Fracture
- Stats based on prescriptions written – all provinces included.
- 40% of Canadians who experience a fracture have a history of prior fracture140% of women with a hip fracture required assistance walking 218% of community dwelling women > 50 years of age who were hospitalized after hip fracture were discharged to long-term care facility.3Hajcsar EE, et al. CMAJ 2000, 163:819-822.Cooper C Am J Med 1997: 103: 12S-19S. Jean S, Bessette L, Belizile EL et al. JBMR 2013; 28:360-71. Ioannidis G, et al. CMAJ 2009;181: 265-271. Hopkins et al. Osteo Intl2012; 23: 921-927
- Speaker notes:Poll participants on their response to the questionResults will be posted on the screen1. The correct answer is A Yes, following WHO definition of OP2. The correct answer is B No, Remind audience: Based on WHO definition of osteoporosis BMD score of less than -2.5 was used to define osteoporosis. New Guidelines recommend assessing risk and deciding on treatment based on assessment of risk factors (age, prior fracture etc) and t-score.
- Speaker notes:BMD alone is not an indication of fracture risk.Fracture rates are higher in those with low T-scores.Population BMD demonstrates that a higher proportion of the population has a BMD in the middle range (-2.0 to -0.5)Fracture rate shows that there is higher rate of fracture in those with OP or a T-score <-2.5, however the number of fractures shows that most fractures occur at T-scores of-2.5 to -0.5. Data demonstrates that BMD alone cannot be used to assess fracture risk.
- Key Points:A focused physical examination, along with the detailed history, identifies risk factors for low BMD, falls and fractures, and can reveal undiagnosed vertebral fractures.In individuals determined to have risk factors, BMD should be measured with dual-energy x-ray absorptiometry(see next slide)Suspected vertebral fractures unrelated to trauma are best defined (on lateral x-rays or by vertebral fracture assessment) as vertebral height loss of 25% or more with disruption of the end plate.Height loss is measured annually, with prospective height loss of >2 cm or historical height loss >6 cm considered significantMeasure height by rib-pelvis distance, occiput to wall distanceThese vertebral fractures are associated with a 5-fold increase in the risk of future vertebral fracturesTimed up-and-go test: Stand up from sitting position without using arms, walk a few paces, return to chair, sit down without using armsThe Timed “Get up and Go Test” is considered unsuccessful if the following occurs:Inability or difficulty performing test Long time (> 14 seconds) to complete2References:Siminoski K et al. The accuracy of historical height loss for the detection of vertebral fractures in postmenopausal women. Osteoporos Int. 2006;17:290-6. Papaioannou A, et al; for the Scientific Advisory Council of Osteoporosis Canada. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ. 2010;182:1864-1873.Timed Up-and-go test. Available at: http://www.saskatoonhealthregion.ca/pdf/03_Timed%20Up%20and%20Go%20procedure.pdf
- Key PointsIndications for measuring Bone Mineral Density (BMD):Aged ≥65 yearsEveryoneAged 50-64 yearsClinical risk factors for fracture (menopausal women, men age 50-64 years)Fragility fracture after age 40 yrProlonged use of glucocorticoids (at least 3 months cumulative therapy in the previous year at a prednisone-equivalent dose ≥7.5mg daily)Use of other high-risk medications (ie. aromatase inhibitors for breast cancer or androgen deprivation therapy for prostate cancer)Parental hip fractureVertebral fracture or osteopenia identified on radiographyCurrent smokingHigh alcohol intake (≥3 units/day)Low body weight (<60kg) or major weight loss (>10% of body weight at age 25 yr)Rheumatoid arthritisOther disorders strongly associated with osteoporosis include: primary hyperparathyroidism, type 1 diabetes, osteogenesisimperfecta, uncontrolled hyperthyroidism, hypogonadism or premature menopause (< 45 years, ), Cushing’s disease, chronic malnutrition or malabsorption, chronic liver disease, COPD and chronic inflammatory conditions (e.g. Inflammatory bowel disease)Aged <50 yearsFragility fractureProlonged use of glucocorticoids (at least 3 months cumulative therapy in the previous year at a prednisone-equivalent dose ≥7.5mg daily)Use of other high-risk medications (ie. aromatase inhibitors for breast cancer or androgen deprivation therapy for prostate cancer)Hypogonadism or premature menopause (age <45 yr)Malabsorption syndromePrimary hyperthyroidismOther disorders strongly associated with rapid bone loss and/or fracturePerform additional biochemical testing to rule out secondary causes of osteoporosis in selected patients.Reference:1. Papaioannou A, et alCMAJ2010;182:1864-1873. 2. Steering Group Communications Feb 9th 2012.
- Key Points:Osteoporosis Canada provides a Guidelines Tool which includes:A calculator for assessing the 10-year Fracture2010 Guidelines (Summary and Full-text)Summary of lab investigations/biochemical tests recommended for patients being assessed for osteoporosisSummary of factors warranting consideration of pharmacologic therapyTherapeutic options (exercise, prevention of falls, calcium, vitamin D, pharmacologic therapy)Reference summary of most important recommendations from 2010 GuidelinesThe FRAX tool is available online to calculate the ten year probability of fracture with BMD. Treat patients at High Risk: >20% risk for a major osteoporotic fracture or >3% risk for a hip fracture.References:OC Guidelines tool available at: http://www.osteoporosis.ca/multimedia/FractureRiskTool/index.html#/HomeFRAX® tool available at: http://www.shef.ac.uk/FRAX/tool.jspNational Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis. 2008. National Osteoporosis Foundation website. Available at: www.nof.org/professionals/NOF_Clinicians_Guide.pdf.
- Key Points:The ROCQ results demonstrated that fragility fractures were often not appropriately recognized and linked to osteoporosis by either patients or their health care practitionersIt is important to fully understand the definition of the fragility fractureReferences:1. Bessette L, et al. Recognizing osteoporosis and its consequences in Quebec (ROCQ): Background, rationale, and methods of an anti-fracture patient health-management programme. Contemp Clin Trials 2008; 29:194-210.2. Brown JP, et al. Validation of a clinical definition of fragility fracture. J Bone Miner Res 2007;23(suppl 1): M350.
- Conditions and medications that increase the risk of falling and potentially fracturing:Benzodiazepines, narcotics, neuroleptics, any anticholinergic associated with: cognitive impairment, confusion, sedation, drowsinessAnticonvulsants, antidepressants, antihypertensives, benzodiazepines, narcotics associated with: dizziness, orthostatic hypotensionAntidepressants, metoclopramide, neurolepticsassociated with: gait abnormalities, Beta-blockers, nitrates, vasodilators associated with: SyncopeNeuroleptics,anticholinergics associated with: Visual Disturbances (blurring)
- Low risk patient: Pharmacologic therapy is not usually required. Lifestyle measures that include exercise, fall prevention, optimization of calcium and vitamin D intake, and smoking cessation are usually sufficient, unless evidence of risk factors for rapid loss of bone mineral density exists.High risk patient: Evidence exists that patients would benefit from pharmacologic treatment.Moderate risk: Patientsshould undergo a careful clinical evaluation to identify additional risk factors. Some of these individuals should be offered pharmacologic therapy. Moderate risk patients may benefit from pharmacotherapy. Reference:Papaioannou A, Morin S, Cheung AM, et al. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ. 2010;182(17):1864-1873.
- Consideration for vertebral fracture assessment or lateral spine X-ray is based on physical examination from earlier screening: Height (measure annually), Rib-to-pelvis distance, Occiput-to-wall distance (kyphosis)Lateral spine X-ray must be used to identify vertebral fracture(s) as VFA is not widely available in CanadaChanges in BMD:Lumbar spine being significantly less than femoral neck is also not precisely defined. Greater than2 T-score standard deviations would be significant. Disorders Associated with Osteoporosis and Increased Fracture RiskPrimary hyperparathyroidismType I diabetesOsteogenesis imperfectaUntreated long-standing hyperthyroidism, hypogonadism, orpremature menopause (< 45 years)Cushing’s diseaseChronic malnutrition or malabsorptionChronic liver diseaseChronic obstructive pulmonary disease (COPD)Chronic inflammatory conditions (e.g., rheumatoid arthritis [RA],inflammatory bowel disease)Drugs Associated with reduction in bone density: Anticonvulsants Antipsychotic drugsAntiretroviral drugsAromatase inhibitorsChemotherapeutic/transplant drugs (i.e. cyclosporine, tacrolimus, platinum compounds, cyclophosphamide, methotrexate)FurosemideGlucocorticoidsHeparin (long-term)Hormonal/endocrine therapies - Gonadotropin-releasing hormone (GnRH) agonists, luteinizing hormone releasinghormone (LHRH) analogs, depomedroxyprogesterone, excessive thyroid supplementationMethotrexateProton Pump Inhibitors (PPI)Selective serotonin reuptake inhibitorsThyroxine (excessive)Long-Term PPI UsePPIs may potentially reduce the absorption of calcium carbonateLong-term PPI use has been associated with an increased risk of hip fractures in retrospective cohort studies, particularly at high doses For patients with osteoporosis using PPIs:Ensure optimal calcium and vitamin D supplementation and instruct patient to optimize food intake of calciumPrescribe the lowest effective PPI dose and review indication and alternatives periodicallyConsider alternate formulation of calcium (eg, calcium citrate) References:Papaioannou A, et al. CMAJ. 2010;182:1864-1873.
- Key Points:All therapeutic options work differently:PTH: appears to have direct actions on osteoblast activity, with biochemical and histomorphometric evidence. PTH activates bone remodeling but still appears to favour bone formation over bone resorption. PTH stimulates insulin-like growth factor-1 (IGF-1) and collagen production and appears to increase osteoblast number by stimulation replication, enhancing osteoblast recruitment and inhibiting apoptosis.SERMs: are estrogen receptor ligands that act like estrogens in some tissues, but block estrogen in others. Thus, SERMs may exhibit an agonistic or antagonistic biocharacter, depending on the context in which their activity is examined. The majority of estrogen effects on bone resorption are mediated through paracrine factors produced by osteopblasts. These actions include 1) increasing IGF-1 and transforming growth factor and 2) suppressing interleukin, tumour necrosis factor and osteocalcin synthesis. The indirect estrogen actions primarily decrease bone resorption.BPs: Pharmacologic agents that control osteoclasts either act directly on the osteoclast or on the bone itself and then are taken up into osteoclasts. When osteoclasts begin to resorb bone that is impregnated with BP, the BP released during resorption impairs the ability of the osteoclasts to form the ruffled border.Denosumab: is a fully human monoclonal antibody with high affinity and specificity for RANKL. When denosumab inhibits the action of RANKL, it reduces the differentiation, activation, and survival of osteoclasts, thereby slowing bone resorption.References:Lindsay R, Cosman F. Osteoporosis. In: Braunwald E, Fauci A, Kasper D, et al., eds. Harrison’s Principles of Internal Medicine. 16th edition. New York: McGraw-Hill; 2005: 2268-2278.Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:337-342.LewieckiEM. RANK ligand inhibition with denosumab for the management of osteoporosis. Expert OpinBiolTher. 2006;6:1041-1050.EVISTA Product Monograph, Eli Lilly, 2008.
- A number of therapeutic options are available in Canada, including antiresorptive agents (bisphosphonates, receptor activator for RANK ligand inhibitor, selective estrogen receptor modulator, hormone therapy, calcitonin) and a bone formation agent.These agents cover a range of dosing and administration options.All therapies reduce the risk of vertebral fractures for postmenopausal women with osteoporosis.In general pharmacotherapy reduces vertebral fracture risk by 30-70%; effect on nonvertebral sites is lower and varies by site.Some interventions prevent nonvertebral and/or hip fractures and may reduce mortality among individuals at high risk.Calcitonin and teriparatide may decrease pain associated with vertebral fractures.For men requiring treatment, alendronate, risedronate, and zoledronic acid can be used as first-line therapies for prevention of fractures.Etidronate and calcitonin may be used as second-line therapy for the prevention of vertebral fractures in menopausal women intolerant of first-line therapies.Grade A evidence defined as: Need supportive level 1 (1year randomized controlled trial with adequate power) or 1+ (systematic overview of meta-analysis of randomized controlled trials) evidence plus consensusReferences:Papaioannou A, et al. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 2010
- Key Points:This slide shows lumbar spine and total hip BMD valuesfrom long-term trials of anti-resorptive therapiesIn all long-term studies, the BMD continues to increase or remains stable over timeIt is important to keep in mind that these are not head-to-head comparisons and results cannot be compared across trials due to different populations and methodsTable is based on the following clinical trials:Risedronate: Vertebral Efficacy with Risedronate Therapy Multinational (VERT-MN)1Alendronate: Fracture Intervention Trial Long-term Extension (FLEX)2Zoledronic acid: The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON)3Denosumab: Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM)4References:Mellstrom D, Sorensen OH, Goemaere S, et al. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int 2004;75:462–468Bone HG, Hosking D, Devogelaer JP, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189-99. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012; 27(2):243-254.Brown JP, Bone HG, Chapurlat R, et al. Six Years of Denosumab Treatment in Postmenopausal Women with Osteoporosis: Results From the First Three Years of the FREEDOM Extension. 2011 ACR Annual Meeting. Presentation L8
- Key Points:These tables present a summary of safety data from the long-term trials of anti-resorptive therapies Results from each trial are summarized below
- Speaker NotesAdditional Safety Information:Bisphosphonates (BPs) may cause upper gastrointestinal disorders and have been linked to esophagitis and esophageal ulcers. To minimize the risk of these adverse events patients should take oral BPs while in an upright position and with the recommended amount of water. Patients should not lie down for at least 30 minutes after taking their medication. Caution should be used when given to patients with active upper gastro-intestinal problems.1,2Osteonecrosis of the jaw (ONJ) has been reported with the use of BPs and denosumab. The majority of cases involved cancer patients treated with high dose IV BPs or high dose denosumab (120 mg every 4 weeks). However, some cases have occurred in osteoporosis patients receiving oral BPs or denosumab 60 mg 6 monthly. A dental examination should be considered in patients with concomitant risk factors. Clinical judgement should guide the management plan of each patient based on individual benefit/risk evaluation.1, 2, 3, 6A recent Atypical Femoral Fractures Task Force Report , recommended that physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labelling of BPs. Although a causal association between BPs and atypical fractures has not been established, recent observations suggest that the risk rises with increasing duration of exposure. 8Zoledronic acid has been associated with renal dysfunction and in rare cases, acute renal failure. Renal deterioration, progression to renal failure and dialysis have been reported rarely in oncology patients after the initial dose of zoledronic acid. It is not recommended for patients with severe renal impairment (creatinine clearance <30mL/min).Teriparatide caused an increase in the incidence of osteosarcoma in rats that was dose and treatment duration dependent at systemic exposures ranging from 3 to 60 times the exposure in humans given a 20-mcg dose. Teriparatide should not be prescribed to patients who are at increased baseline risk for osteosarcoma.In a denosumab study, serious infections were 4.1% in denosumab subjects compared to 3.4% in placebo subjects. Serious skin infections were reported more frequently in the denosumab (0.4%) versus the placebo (<0.1%) groups; predominantly cellulitis. Endocarditis was also reported in <0.1% denosumab group; 0% placebo group. The incidence of opportunistic infections was balanced between denosumab and placebo groups and the overall incidence of skin infections was similar between the denosumab (1.5%) and placebo (1.2%) groups. Patients should be advised to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis and erysipelas.Denosumab therapy results in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry. The significance of these findings and the effect of long-term treatment with denosumab are unknown. Monitor patients for osteonecrosis of the jaw, atypical fractures, and delayed fracture healing .References:Fosamax® (alendronate sodium) Product Monograph, Merck Frosst Canada Ltd., October 8, 2009.Actonel® (risedronate sodium) Product Monograph, Warner Chilcott Co Canada, February 16, 2010.Aclasta® (zoledronic acid) Product Monograph, Novartis Pharmaceuticals Canada, Inc., September 21, 2009. Evista® (raloxifene hydrochloride) Product Monograph, Eli Lilly Canada Inc., October 10, 2008. Forteo® (teriparatide [rDNA origin] injection) Product Monograph, Eli Lilly Canada Inc., February 9, 2010.ProliaTM (denosumab) Product Monograph, Amgen Canada Inc., August 6, 2010.Shenker NG, Jawad ASM. Bisphosphonates and osteonecrosis of the jaw. Rheumatology 2007;46:1049-1051.Shane E, Burr D, et al Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Report of a Task Force of the American Society for Bone and Mineral Research Running Title: Atypical Femoral Fractures Task Force Report. JBMR 2010: On line Sept 7, 2010. DOI 10.1002/jbmr.253
- Notes: Understanding the reported incidence of infrequent events, some context to adverse events in the treatment of osteoporosis may need to be put into context for physicians and patients. The incidence of fatal motor vehicle accidents reports in Canada in 2007 was 8.4 events / 100 000 population. The rate increases further to 12.2 event / 100 000 licensed population. 1The Canadian homicide rate in 2009 as reported by Statistics Canada was 1.8 homicides / 100 000 population. 2Using age-adjusted rates, we estimated that for every 100 or so reduction in typical femoral neck or intertrochanteric fractures, there was an increase of one subtrochanteric fragility fracture. (Wang et al JBMR 2011)References: Canadian Motor Vehicle Traffic Collision Statistics: 2007. Transport Canada Road Safety and Motor Vehicle Regulation . TP 3322 Cat. T45-3/2007ISBN 978 . 2007 Casualty Rates. http://www.tc.gc.ca/eng/roadsafety/tp-tp3322-2007-1039.htm#t5Statistics Canada. 2009 Homicide Rate. http://www40.statcan.ca/l01/cst01/Legal12b-eng.htmKhan A, et al. Bisphosphonate-associated osteonecrosis of the jaw: An Ontario Survey. ASMBR, Toronto, 2010. Poster SA0384.Dell R, et al. A retrospective analysis of all atypical femur fractures seen in a large California HMO from the years 2007 to 2009 . JBMR 2010. 25(Suppl1):61. Abstract 1201Johnell O, Oden A, Caulin F, Kanis JA. Acute and long-term increase in fracture risk after hospitalization for vertebral fracture. Osteoporos Int. 2001;12(3):207-14. Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. 2006;17:1726-1733. Burge R, Dawson-Hughes B, Solomon DH, et al. A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22:465-475.
- Speaker notes:Poll participants on their response to the questionResults will be posted on the screenNo correct answer
- Key Points1: Simple biochemical screening should be considered in all patients with documented osteoporosis prior to initiating pharmacologic treatmentCalcium and Vitamin D1:Recently published Osteoporosis Canada guidelines for vitamin D have emphasized the high prevalence of vitamin D insufficiency in the population and the importance of recommending supplements to ensure optimal vitamin D status Vitamin D insufficiency should be considered in any patient with osteoporosis, particularly when there are recurrent fractures, bone loss despite therapy or with co-morbid conditions such as celiac disease or gastric bypass that affect vitamin D absorption or action In individuals receiving pharmacologic therapy for osteoporosis, measurement of serum 25-OH-D should follow three to four months of an adequate supplementation dose and should not be repeated if optimal level (>75 nmol/L) is achieved.Additional Tests PTH: for Hyperparathyroidism - if persistently elevated serum calcium Protein electrophoresis and/or Immunoelectrophoresis: for Multiple myeloma- in patients with multiple or atypical vertebral fractures Antibodies associated with gluten enteropathy: For Celiac disease - if symptoms/signs of malabsorption or non-response to vitamin D therapy 24 hour urine for calcium: Hypercalciuria - consider in patients with history of kidney stones or high dose glucocorticoids for prolonged periodsReferences:Papaioannou A, Morin S, Cheung AM, et al. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ. 2010;182(17):1864-1873.
- ACTONEL DR INFORMATIONWARNINGS AND PRECAUTIONS - GastrointestinalBisphosphonates may cause upper gastrointestinal (GI) disorders such as dysphagia, esophagitis, esophageal ulcer, and gastric ulcer (see ADVERSE REACTIONS). Since some bisphosphonates have been associated with esophagitis and esophageal ulcerations, to facilitate delivery to the stomach and minimize the risk of these events, patients should take ACTONEL and ACTONEL DR while in an upright position (i.e., sitting or standing) and with sufficient plain water (> 120 mL). Patients should not lie down for at least 30 minutes after taking the drug. Healthprofessionals should be particularly careful to emphasize the importance of the dosing instructions to patients with a history of esophageal disorders (e.g., inflammation, stricture, ulcer, or disorders of motility).ADVERSE REACTIONSIn ACTONEL and ACTONEL DR osteoporosis studies, the most commonly reported adverse reactions were abdominal pain, dyspepsia and nausea. In addition, diarrhea was the most commonly reported adverse reaction for the highest ACTONEL monthly dose. Dosing ConsiderationsACTONEL (risedronate sodium) film-coated tablets ACTONEL should be taken on an empty stomach at least 30 minutes before consuming the first food, drink (other than plain water) and/or any other medication of the day. Food, medication or drink other than plain water can interfere with the absorption of ACTONEL. Each ACTONEL tablet should be swallowed whole while the patient is in an upright position and with sufficient plain water (> 120 mL) to facilitate delivery to the stomach. Patients taking ACTONEL should not lie down for at least 30 minutes after taking the medication (see WARNINGS AND PRECAUTIONS, General). ACTONEL tablets should not be chewed, cut, or crushed. Medications containing polyvalent cations (e.g. calcium, magnesium, aluminum, and iron) can interfere with the absorption of ACTONEL. These medications should be administered at a different time of the day than ACTONEL.ACTONEL DR (risedronate sodium) delayed-release tablets ACTONEL DR should be taken in the morning, with breakfast, (this may include high fat foods, coffee, tea, milk, orange juice, etc. A higher incidence of upper abdominal pain was seen when ACTONEL DR was taken in a fasted state before breakfast. Each ACTONEL DR tablet should be swallowed whole while the patient is in an upright position and with sufficient plain water (>120 mL) to facilitate delivery to the stomach. Patients taking ACTONEL DR should not lie down for at least 30 minutes after taking the medication ACTONEL DR tablets should not be chewed, cut, or crushed. Care should be taken not to break the outer coating which is designed to remain intact until the tablet reaches the small intestine where the tablet coating dissolves and releases the active ingredient Calcium supplements and antacids can interfere with the absorption of ACTONEL DR. These medications should be administered at a different time of the day than ACTONEL DR.Reference:Actonel® and Actonel DR® Product Monograph, July 2011USE OF BPs with PPIsThree large studies using administrative databases have implicated the use of proton pump inhibitors as a risk factor for hip fractures.• The relation between the use of proton pump inhibitors and fracture may involve calcium malabsorption due to induced hypochlorhydria, but this remains unproven.• These retrospective administrative database studies should be confirmed by randomized controlled trials or prospective cohort studies.• Clinicians must weigh the proven benefits of proton pump inhibitors when appropriately prescribed against the potential risk of osteoporotic fracture.Targownik LE, Lix LM, Metge CJ, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008;179:319-26.
- Key Points:For patients in which an alternative therapy is deemed appropriate, it is important to understand the impact of switching on safety and efficacy outcomesThis slide displays efficacy results from two studies where patients switched from alendronate therapy to an alternative therapy, densoumab (left) or zoledronic acid (right)After switching from alendronate, denosumab increases BMD1 and zoledronic acid maintains2 BMD at lumbar spineIn both cases, there was no increase in adverse events upon switching therapies1,2Study Transitioning from Alendronate to Denosumab (STAND)1(Figure on left)The STAND (Study of Transitioning from AleNdronate to Denosumab), is a Phase 3 double-blind, double-dummy study in women previously treated with alendronate, which evaluated the effects of transitioning to denosumab on changes in BMD (primary endpoint of BMD at total hip)All patients received 70mg weekly branded alendronate for 1 month, then were randomized 1:1 to receive SC denosumab injections (60 mg every 6 months [q6m]) and an oral placebo or oral alendronate weekly (70 mg qw) and a placebo SC injection every 6 months.There was no washout period between transitioning from alendronate to denosumab. Patients had a mean duration of alendronate use of 3 years prior to the study.Total hip BMD increased by 1.90% (95% CI: 1.61%, 2.18%) from baseline at Month 12 in subjects transitioning to denosumab compared with a 1.05% (95% CI: 0.76%, 1.34%) increase from baseline in subjects continuing on alendronate therapy. There were also significantly greater gains in BMD observed at Month 12 at the lumbar spine, femoral neck, and one-third radius with denosumab therapy compared with alendronate therapy.Denosumab was found to be non-inferior to alendronate based on total hip BMD changes.1Non-inferiority was based on a pre-specified lower threshold of the 95% CI being > –0.35%.1The difference between denosumab and alendronate was 0.85% (95% CI: 0.44%, 1.25%).1It was pre-specified that superiority of the total hip BMD at month 12 would be tested if denosumab demonstrated to be not inferior to alendronate.1Superiority testing demonstrated the increase in total hip BMD with denosumab was statistically superior to alendronate (P < 0.0001).1Significantly greater increases n BMD with denosumab were also demonstrated at the lumbar spine, femoral neck and one third radius. Study Transitioning from Alendronate to Zoledronic Acid2(Figure on right)This Phase 3, randomized, double-blind, double-dummy trial assessed the safety and efficacy of a single dose of IV zoledronic acid (ZOL) 5 mg vs. oral alendronate (ALN) 70 mg weekly in postmenopausal women with low bone mineral density (BMD) who had previously been treated with ALN.2The inclusion criteria for this study was postmenopausal women who were receiving oral ALN for at least 1 year immediately prior to randomization and with lumbar spine or femoral neck BMD T-score values ≤ −2.0 prior to initiation of ALN.2Patients were randomized to one 15 min intravenous (IV) infusion of ZOL 5 mg plus 52 weeks of oral placebo (n = 113), or one IV infusion of placebo plus 52 weeks of oral ALN 70 mg (n = 112). No wash out period was included. End points included percentage change in lumbar spine BMD from baseline to Month 12, and relative change from baseline in BTMs.The study concluded that a single infusion of ZOL 5 mg maintained BMD for 12 months following the switch from oral ALN (mean duration of 4 years) in women with osteoporosis.A small increase in BMD from baseline occurred for both treatment groups.BMD remained essentially unchanged in both groups over the 12-month study. Change from baseline to Month 12: ZOL (0.167%, SE = 0.258) and ALN (0.813%, SE = 0.283).References:Kendler DL, Roux C, Benhamou CL, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. J Bone Miner Res. 2010;25:72-81.McClung M, Recker R, Miller P, et al. Intravenous zoledronic acid 5 mg in the treatment of postmenopausal women with low bone density previously treated with alendronate. Bone. 2007;41:122-128
- Key Points: Patient support programs offer services designed to help improve adherence There are a number of patient support programs available:Osteoporosis CanadaHealthandBone.caDrugcoverage.caProvitalReferences:For My Bones Program. Available at: https://www.formybones.ca/help_en.do. Accessed October 2010 report Patient Direct, ProVital ™ Program. Available at: http://www.provital.ca. Accessed Nov 30, 2011. Patient Direct, ProVital ™ Program, as at Nov 30, 2011 report. Osteoporosis Canada. Available at: http://www.osteoporosis.ca. Accessed November 2010. Health and Bone. Available at: http://www.healthandbone.ca/en/home. Accessed November 2010. Drug Coverage.ca Available at: http://www.drugcoverage.ca Accessed October 2010.