Osteoporosis Management: Translating Research Into Optimal Fracture Protection

1. Osteoporosis Management: TranslatingResearch Into Optimal Fracture Protection

2. Osteoporosis in Women Accounts for More Disability and Direct Hospital Costs Than Many Other Diseases 600 548,615 500 400 353,654 352,062 Number of hospital bed days (thousands) 300 200,669 200 131,331 100 0 Osteoporosis COPD Stroke Breast MI carcinoma Lippuner K, et al. Osteoporos Int 1997;7:414–425

3. The Incidence of Osteoporotic Vertebral and Hip Fractures is Higher in Women Than in Men and Increases With Age Men Women 400 400 Hip Radiographic vertebral 300 300 Wrist 200 200 Rate per 10,000 per Year 100 100 0 0 >85 >85 50–54 55–59 60–64 65–69 70–74 75–79 80–84 50–54 55–59 60–64 65–69 70–74 75–79 80–84 Age (Years) Age (Years) Data from Europe 1988–1998 Sambrook P, Cooper C. Lancet 2006;367:2010–2018

4. Risk Factors for Osteoporotic fractures Genetic/Non-modifiable Age Female sex Asian or white ethnicity Previous fragility fracture Family history of hip fracture or osteoporosis Small frame Potentially Modifiable Menopause-related estrogen deficiency Low body weight Calcium/vitamin D deficiency Inadequate physical activity Excessive alcohol intake Cigarette smoking Long-term steroid therapy (secondary osteoporosis) National Osteoporosis Foundation (NOF). Available at: http://www.nof.org/osteoporosis/diseasefacts.htm.Accessed August 31, 2007. 4

5. Diagnosis of Osteoporosis • Patient history, for detection of etiology and risk factors of osteoporosis. • Initial physical examination, signs of dorsal kyphosis could be the consequence of vertebral compression fractures. • X-rays or other medical imaging techniques to detect skeletal pathology and fractures. • Measurement of BMD to assess low bone mass • Laboratory tests measuring biochemical markers of bone turnover. [NIAMS Osteoporosis Diagnosis, p1].

6. Recommendations for Bone Mineral DensityTesting • All women aged 65 years or older, regardless of other risk factors for osteoporosis. • Postmenopausal women younger than 65 years who have at least 1 risk factor for osteoporosis other than menopause, eg: • Family history of osteoporosis. • Personal history of low trauma fracture at age >45. • Current smoking. • Low body weight (< 127 lb). • All postmenopausal women who have experienced a fragility fracture. According to NOF guidelines, Delaney 2006, pS13

7. WHO Bone Density Criteria for Osteoporosis T-score = units of standard deviation (SD) that a patient’s BMD is above or below mean peak bone mass for a young adult woman, measured at the spine or hip. Reduction by 1 SD equals a 10%–12% decrease in BMD. 1 SD change increases fracture risk by 1.5- to 2.5-fold. Diagnosis BMD T-Score No lower than −1 Between −1 and −2.5 −2.5 or less −2.5 or less with fragility fractures Normal Low bone mass [osteopenia] Osteoporosis Severe osteoporosis Adapted from WHO Technical Report Series 921. Geneva: World Health Organization; 2003. 7

8. Real-World Obstacles in the Management of Osteoporosis • Silent disease; some fractures may initially go unnoticed. • Insufficient rates of diagnosis and treatment. • Poor adherence to prescribed doses: • Low persistence over time • Lack of compliance with dosing instructions Southern Medical Journal • Volume 99, Number 6, June 2006 The Journal of Family Practice, Vol 59, No 6 | JUNE 2010

9. Compliance and persistence with Oral Bisphosphonates are poor and suboptimal in clinical practice1 100 90 80 70 Daily 60 Weekly % of Patients 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 Months of Continuous Persistence 2 P = NS 1. VéroniqueRabenda , Poor adherence to oral bisphosphonate treatment and its consequences: a review of the evidence, Expert Opin. Pharmacother. (2009) 10(14):2303-2315 2. Downey TW, et al. South Med J 2006;99:570-575. 9

10. Determinants of Poor Persistence 1. Emkey RD, Ettinger M. Am J Med. 2006;119:S18–S24. 2. Cramer JA, Silverman S. Am J Med. 2006. 3. Downey TW, et al. South Med J. 2006;99:570–575. 4. Gold DT, et al. Ann Pharmacother. 2006. 5. Sambrook P. AustFam Physician. 2006;35:135–137. 10 Poor persistence is particularly associated with complex administration and frequent dosing1,2 To improve persistence, eliminate the causes of poor persistence.

11. Rationale for Less-Frequent and Easier-to-Follow Dosing Regimens Poor adherence to daily, weekly, and monthly regimens of oral bisphosphonates may result in compromised effectiveness. 1 A once-yearly IV bisphosphonate therapy can deliver real-world effectiveness by assuring adherence for the entire annual dosing interval 2 1-The Journal of Family Practice, Vol 59, No 6 | JUNE 2010 2- Black DM, et al. N Engl J Med. 2007;356:1809-1822 11

12. Summary of FDA Approved Indications for Osteoporotic Therapies Supplement to Journal of Managed Care Pharmacy JMCP May 2012 Vol. 18, No. 4-b

13. 0.5 0.4 0.3 0.2 0.1 0.0 Zoledronic acid:Key Pharmacological Characteristics Binding to Hydroxyapatite1 • High binding affinity for bone in vitro • Maximizes attachment • Minimizes detachment • Potent FPP synthase inhibition in vitro • Maximizes antiresorptive potential • Minimizes total amount of drug required • Allows single administration of total annual dose 4 3 KL (L/mol x 106) 2 1 0 CLO ETD RIS IBA ALN ZOL FPP synthase2 IC50 (mM) ALN IBA RIS ZOL • Nancollas GH, et al. Bone. 2006;38:617-627. • Dunford JE, et al. J Pharmacol Exp Ther. 2001;296:235-242. 14

14. Zoledronic Acid Clinical Trials:Past, Present and Future PUBLISHED Zoledronic Acid For Paget’s Disease PUBLISHED HORIZON Pivotal Fracture Trial (PFT) HORIZON Recurrent Fracture Trial (RFT) PUBLISHED HORIZON Pivotal Fracture Trial (PFT): Bone remodeling • PUBLISHED • HORIZON • Glucocorticoid-induced Osteoporosis (GIO) Trial • HORIZON PFT Trial (Subgroup Analysis) PUBLISHED HORIZON PFT extension study 2005–6 2007 2008 2009–10 2012

15. Long-term Treatment of Patients with Osteoporosis Zoledronic Acid Extension Study

16. Journal of Bone and Mineral Research, 2012

17. HORIZON-PFT Extension:Objectives • Maintain BMD • Provide additional fracture protection • Reinforce the safety profile established for 3 years of ZOL therapy PFT = pivotal fracture trial, Dennis Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 • A 3-year extension of the 3-year HORIZON-PFT study was performed to address whether increasing the duration of therapy beyond 3 years will:

18. Patient Flow From Core Study to Extension Core study N = 7,736 HORIZON-PFT core study (3 years) Placebo N = 3,876 ZOL N = 3,889 1,221 assigned to ZOL to maintain blinding (follow up <3 years) P3Z3 Randomized in extension N = 1,233 Extension (3 years) ZOL N = 617 Z6 Placebo N = 616 Z3P3 Dennis Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to t he HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 19

19. HORIZON-PFT Extension: Study Overview International, multicenter, double-blind, placebo controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n.616) or placebo (Z3P3, n.617). All patients received daily oral calcium (1000 to 1500 mg) and vitamin D (400 to 1200 IU). *All patients received calcium 1000–1500 mg/d and vitamin D 400–1200 IU/d and follow-up telephone calls every 3 months. FN: femoral neck, BTMs ;bone turn over markers, PBO = placebo, ZOL = zoledronic acid, Dennis Black, University of California, San Francisco, USA, The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

20. HORIZON-PFT Extension: End Points Primary endpoint: Percentage change in FN BMD at Year 6 vs. Year 3. Secondary endpoints: BMD at other sites, BTMs, fracture incidence & safety. *All patients received calcium 1000–1500 mg/d and vitamin D 400–1200 IU/d and follow-up telephone calls every 3 months. FN: femoral neck, BTMs ;bone turn over markers, PBO = placebo, ZOL = zoledronic acid, Dennis Black, University of California, San Francisco, USA, The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

21. HORIZON-PFT Extension: Inclusion and Exclusion Criteria • Key inclusion criteria1 • Postmenopausal women aged ≤ 93 years who received all 3 infusions of study drug in the Core study. • Randomized ≤ 13 weeks after completing the Core study. • Key exclusion criteria2 • Pregnancy. • Prior use of IV bisphosphonate, strontium, sodium fluoride, PTH. • Use of oral bisphosphonate, systemic corticosteroid, anabolic steroid or growth hormone without sufficient washout. • Serum calcium < 2 or > 2.75 mmol/L at Core study last visit. • Renal insufficiency with CrCl < 30 mL/min or urine dipstick > 2+ protein. CrCl = creatinine clearance; IV = intravenous; PTH = parathyroid hormone; SCr = serum creatinine. 1. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 2. Black DM, et al. N Engl J Med. 2007;356:1809–1822.

22. Characteristics and Bone Parameters at Extension Study Baseline • On average, patients were 75.5 years old, with >50% having femoral neck BMD T-scores lower than 2.5 and approximately 60% with at least one vertebral fracture. • Baseline characteristics between the Z3P3 and Z6 groups were similar. *Missing values: Z6, n = 2;Z3P3, n = 2. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

23. Efficacy Data from the HORIZON-PFT Extension Study

24. 6 Years of Continuous ZOL Treatment Resulted in Significant Gains in Femoral • Neck BMD Z6 Z3P3 5 1.36% +4.5% (0.58, 2.15) P = 0.0007 4 3 +3.1% Change from Baseline (%) 2 Start of extension 1 Core Study Extension Study 0 0 1 2 3 4 5 6 Time (Years from Core Study Baseline) ITT = intention to treat. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

25. Change in Total Hip BMD at Year 6 Relative to Core Baseline (ITT)* Z6 Z3P3 8 7 6 5 1.47% P < 0.0001 Change from Baseline (%) 4 3 2 1 Core Study Extension Study 0 0 1 2 3 4 5 6 Time (Years) * ITT = intention to treat. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

26. Change in Lumbar Spine BMD at Year 6 Relative to Core Baseline (ITT)* Z6 Z3P3 14 12 10 2.06% 8 Change from Baseline (%) 6 4 Start of extension 2 0 Core Study Extension Study –2 0 1 2 3 4 5 6 Time (Years from Core Study Baseline) *ITT = intention to treat. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254, P = 0.19

27. Significantly Fewer New Morphometric Vertebral Fractures in ZOL Continuation Than Discontinuation (ITT)** Z3P3 Z6 PBO ZOL Core Study (Yr 0–3) 15 70%† For fractures, we saw 49% lower risk for morphometric vertebral fractures but no significant difference in clinically evident vertebral fractures or nonvertebral fractures. 10 Patients with New Vertebral Fracture (%) 49%* 5 0 Core Study1 Extension Study2 1233 randomized to Extension • ** ITT = intention to treat. Core study:†P < 0.001 relative risk reduction vs. placebo (PBO). *P =0.0348,relative risk reduction vs Z3P3; n = the number of patients in the analysis population with X-rays at Year 3 and Year 6 ITT = intention to treat , Z3P3 = ZOL for 3 years and placebo for 3 years, Z6 = ZOL for 6 years. 1. Black DM, et al. N Engl J Med. 2007;356:1809–1822. 2. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

28. Taken together, these efficacy results show that continuing ZOL for 6 years maintains early gains in BMD and, by implication, bone strength, but discontinuation after 3 years also maintains substantial residual benefit. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

29. Change in Serum PINP with 6 vs. 3 Years Zoledronic Acid (ITT) 60 Z6 Z3P3 Time of infusion Start of extension Absolute difference at Year 6 3.0 ng/mL (P = 0.0001) 40 28.8 * * Mean PINP (ng/mL) 20 25.8 Core Study Extension Study 0 0 1 2 3 4 5 6 Time (Years) Mean values remained within the premenopausal reference range throughout PINP: Procollagen type I N-terminal propeptide, Horizontal dashed lines in green represent premenopausal reference range (adapted from Black DM, et al. N Engl J Med. 2007;356:1809–1822) Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

30. Change in BSAP with 6 vs. 3 Years Zoledronic Acid (ITT) Z6 Z3P3 20 15 Time of infusion Absolute difference 0.14 ng/mL P =0.74 (Y0-Y6) Z3P3 9.1% 10 Mean level (ng/mL) Z6 9.0% 5 0 0 1 2 3 4 5 6 Time (Years) BSAP: Bone specific alkaline phosphatase , Horizontal dashed lines in green represent premenopausal reference range (adapted from Black DM, et al. N Engl J Med. 2007;356:1809–1822). Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

31. Change in β-CTX with 6 vs. 3 Years Zoledronic Acid (ITT) 0.6 Z6 Z3P3 0.4 Start of extension Time of infusion Absolute difference Year 0–6 0.03 ng/mL (P = 0.45) 0.4 Mean β-CTX (ng/mL) 0.3 0.18 0.2 0.16 0.1 Core Study Extension Study 0 0 1 2 3 4 5 6 Time (Years) Mean values remained within the premenopausal reference range throughout. Horizontal dashed lines in green represent premenopausal reference range (adapted from Black DM, et al. N Engl J Med. 2007;356:1809–1822) Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

32. 6 Years of ZOL Treatment Maintains Reduction in β-CTX at a Lower Level Than 3 Years of Treatment (ITT) 0.8 Z3P3 Z6 0.6 Start of extension trial 0.4 Mean β-CTX (ng/mL) 0.3 * 0.2 0.1 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 Time (years) Mean values remained within the premenopausal reference range throughout. ß-CTX :Beta C-terminal type 1 collagen telopeptide, *P < 0.05. No significant difference at any other time point in the extension study. Horizontal dashed lines represent premenopausal reference range (Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822). Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

33. Safety Data from the HORIZON-PFT Extension Study

34. Overall Safety Results of the Extension Study No increase in risk of AEs or SAEs with long-term (6-Year) ZOL treatment compared with 3 years of treatment AE = adverse event; PMO = postmenopausal osteoporosis; SAE = serious adverse event. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

35. Zoledronic Acid: Long-Term Safety In general, safety was similar in those continuing ZOL compared with those who discontinued. In the extension trail , rates of post dose symptoms were much lower than active group rates in the core study and not significantly different between randomized groups. Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 38

36. There were significantly more short-term rises in serum creatinine 9 to 11 days after infusion in the Z6 versus the Z3P3 group, but these short-term increases quickly resolved; There was no difference between treatment groups in mean change in creatinine clearance and there were no long-term differences in any aspect of renal function. Renal Safety Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 39

37. Selected Cardiovascular Events The difference in cardiovascular events in the Z6 (2.0%) versus Z3P3 (1.1%), was not statistically significant (P: 0.26). TIA = transient ischaemic attack. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

38. Bone Safety • No cases of atypical femur fracture or hip or knee avascular necrosis. • One case of ONJ reported from a patient with risk factors in Z6 which was resolved with appropriate treatment. • In non-randomized group (P3Z3): • 1 ONJ case with several ONJ risk factors. • 1 Subtrochanteric fracture with no atypical features. *Events were new events that occurred during the extension trial. †Results for the Pivotal Fracture Trial are from a secondary analysis that reviewed fracture records and radiographs (when available) from all hip and femur fractures to identify those below the lesser trochanter and above the distal metaphyseal flare and to assess atypical features. 1. Grbic JT, et al. JADA. 2008;139:32–40; 2. Black DM, et al. N Engl J Med. 2010; 362:1761–1771. 3. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

39. Summary of HORIZON-PFT Extension Study

40. HORIZON-PFT Extension Study: Efficacy Summary • Long-term efficacy results showed that 6 years of ZOL treatment led to: • Significantly greater increases from baseline in femoral neck and total hip BMD than discontinuation at 3 years. • Significant risk reduction in vertebral morphometric fracture risk vs. discontinuation at 3 years. • Maintenance of BTMs within reference range. • Losses in BMD and BTMs in discontinuation group were modest • Residual benefits after discontinuation suggests that some patients may discontinue infusions for up to 3 years. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

41. HORIZON-PFT Extension Study: Safety Summary Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 • Safety results were similar in those continuing ZOL vs. those who discontinued: • Rates of post-dose symptoms were similar and much lower than that in ZOL group in the Core study. • There is no significant increase in the risk of atrial fibrillation with ZOL treatment. • ZOL treatment for 6 years showed no overall impact on renal function: • Significantly more transient rises in SCr 9–11 days after infusion in patients who continued ZOL that quickly resolved.

42. Clinical Implications of the Extension Study: Who Should Remain on Treatment? Post hoc Analysis

43. Clinical Recommendation • 6-year data support a positive benefit/risk for long-term ZOL therapy. • A post hoc analysis provides insights on which patients: • May benefit most from continued treatment beyond 3 years. • May be considered for treatment discontinuation for up to 3 years. • Decision to continue or interrupt ZOL therapy beyond 3 years should be made on an individual patient basis. FDA Advisory Committee. September 9, 2011: Joint Meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM271911.pdf 46

44. Clinical Recommendation • The existing data do not support a specific limitation on the duration of use of Aclasta for all osteoporosis patients. • However, based on the reduction in morphometric fractures, those who are at high fracture risk, ( existing vertebral fractures or with hip osteoporosis after an initial course of therapy), may benefit from continued annual infusions. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 FDA Advisory Committee. September 9, 2011: Joint Meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM271911.pdf

45. To avoid noncompliance problems and the associated increase in fracture risk, consider IV bisphosphonates for first-line therapy in women with postmenopausal osteoporosis. The intermittent dosing regimens of IV bisphosphonates ensure 100% persistence throughout the dosing interval. • Consider IV Bisphosphonates for First-line Therapy Adapted from The Journal of Family Practice, Vol 59, No 6 | JUNE 2010 , Postmenopausal osteoporosis: Another approach to management 48

46. NEW Zoledronic Acid Efficacy In Prevention Of Postmenopausal Osteoporosis

47. Preventing fragility fractures is an important public health objective • Fragility fractures are associated with increased morbidity and mortality, so an effective fracture prevention strategy would have a major impact on morbidity and a smaller but important impact on mortality in older adults.1–3 • In the United States, approximately 10 million women have osteoporosis and another 34 million have low bone mass (osteopenia).4 • 1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785–95. • 2. Miller RG. Osteoporosis in postmenopausal women. Therapy options across a wide range of risk for fracture. Geriatrics2006;61:24–30. • 3. Brown JP, Josse RG, 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada [published errata appear in CMAJ 2003;168:400, CMAJ 2003;168:676, and CMAJ 2003;168:544]. CMAJ. 2002;167 (10 Suppl): S1–34. • 4. National Osteoporosis Foundation 2008. Available at: http://www.nof.org/osteoporosis/diseasefacts.htm.Retrieved December06, 2009. • References 1-4 are stated in McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. ObstetGynecol2009; 114 (5): 999-1007.

48. Although women with low bone mass have a lower fracture risk compared with women of the same age with osteoporosis, they are at risk for developing osteoporosis unless bone loss is prevented. • Zoledronic acid has been evaluated for the prevention of PMO in a 2 year study. • The study compared a single ZOL acid infusion or two annual infusions with PBO (McClung 2009).

49. STUDY DESIGN • 24 ‐ month, multicenter, randomised, double‐blind, placebo‐controlled, parallel group clinical trial in the prevention of bone loss in postmenopausal women with osteopenia. McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. ObstetGynecol2009; 114 (5): 999-1007.

50. OBJECTIVES • To demonstrate that zoledronic acid given at randomization and at Month 12 or given at randomization only was superior to placebo in % change in lumbar spine BMD at Month 24 in women stratified by time since menopause(<5years or≥5years). McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. ObstetGynecol2009; 114 (5): 999-1007.