Disclosures. Bisphosphonate Treatment for Osteoporosis: Do the Benefits Outweigh the Risks? Risks vs Benefits. Bisphosphonates: Benefits and Risks

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1 Bisphosphonate Treatment for steoporosis: Do the Benefits utweigh the Risks? 37 th Annual Advances in Internal Medicine May 18 and June 22, 29 hsponsored resentations Disclosures Eli Lilly & Company, GlaxoSmithKline, Merck & Company, ovartis, rocter & Gamble harmaceuticals, Roche, sanofi-aventis, Wyeth hconsultation Steven T Harris MD FAC Clinical rofessor of Medicine University of California, San Francisco Amgen, Eli Lilly & Company, GlaxoSmithKline, Merck & Company, ovartis, rocter & Gamble, Roche, sanofi-aventis, Wyeth Bisphosphonates: Benefits and Risks Risks vs Benefits hefficacy Short-term efficacy usually established on the basis of fracture risk reduction over 3 years Long-term efficacy (Is treatment forever? ) hsafety Short-term concerns Long-term concerns that have been raised hcost both economic and quality of life hsteonecrosis of the jaw (J) hatrial fibrillation habnormal bone quality/atypical fractures hesophageal cancer

2 FDA-Approved Therapeutic ptions in the USA revention Stops bone loss Estrogen Treatment Reduces vertebral fractures Calcitonin (Miacalcin, Fortical ) Alendronate (Fosamax ) Risedronate (Actonel ) Ibandronate (Boniva : oral, injection) Zoledronic acid (Reclast : infusion) Raloxifene (Evista ) TH (Forteo ) on-itrogen-containing Bisphosphonates CH 3 H Etidronate Cl Cl Clodronate itrogen-containing Bisphosphonates Alkyl H 2 H 2 CH 3 H amidronate H Alendronate H Ibandronate Heterocyclic H Risedronate H Zoledronic acid Bisphosphonates Alendronate, Risedronate, Ibandronate and Zoledronic Acid A number of different bisphosphonates are now available for the prevention and treatment of osteoporosis in daily oral, intermittent oral and intermittent parenteral formulations: h Alendronate 1 mg daily or 7 mg weekly for treatment, mg daily or 3 mg weekly for prevention h Risedronate mg daily or 3 mg weekly; 7 mg on two consecutive days once each month, 1 mg monthly h Ibandronate 2. mg daily or 1 mg monthly by mouth; 3 mg iv over 1-3 seconds every 3 months h Zoledronic acid mg by infusion over a minimum of 1 minutes every year Bisphosphonates: Indications Alendronate, Risedronate, Ibandronate and Zoledronic Acid h Treatment and prevention of postmenopausal osteoporosis (alendronate, risedronate and ibandronate) h Treatment of postmenopausal osteoporosis (zoledronic acid) h Treatment and prevention of glucocorticoid-induced osteoporosis (risedronate, zoledronic acid) h Treatment of glucocorticoid-induced osteoporosis (alendronate) h Treatment of men with low bone density (alendronate, risedronate, zoledronic acid)

3 Bisphosphonates: 24-month BMD Changes Trials of Different Agents Cannot Be Compared Directly % Change in BMD 7 6 RIS 3 mg weekly1 4 AL 7 mg weekly1 3 IB 1 mg monthly 2 ZL mg iv annually Spine Total Hip Fracture Endpoints hregulatory approval of existing medications has been based on fracture reduction, rather than changes in surrogates such as bone mineral density (BMD) alone hwith the exception of the annual infusion of zoledronic acid, the approval of all current bisphosphonates has been based on pivotal trials conducted with daily therapy hthere are no controlled trials showing that weekly or monthly bisphosphonate therapy reduces fracture risk; the results of daily therapy have been bridged to weekly and monthly therapy 1 Bonnick S, et al. J Clin Endocrinol Metab 26;91: Reginster J-Y, et al. Ann Rheum Dis 26;6: Black DM, et al. Engl J Med 27;36: Fracture Endpoints, con t hthe most common fracture endpoint has been the reduction in vertebral fracture Vertebral fracture has most often been defined by morphometric changes, including both new and worsening fractures Clinical vertebral fracture defined as fracture associated with back pain has usually been identified as a secondary endpoint h on-vertebral fracture has most commonly been identified as a secondary endpoint as well Varying definitions of non-vertebral fracture : all fractures vs fragility fractures vs a particular composite endpoint of fractures Hip fracture has sometimes but not always been identified as a separate endpoint of particular interest Fracture Endpoints, con t hfracture reduction has most often been expressed both clinically and commercially as relative risk reduction, rather than absolute risk reduction hthe rapidity with which fracture protection occurs has been of clinical and commercial interest hthere are no head-to-head randomized trials with fracture as the primary endpoint hthe pivotal fracture trials recruited patients with a certain sameness but there were notable differences in demographics, baseline fracture status and baseline BMDs nevertheless There were obvious differences in observed fracture rates both vertebral and non-vertebral

4 Bisphosphonates: Clinical Trial Results Trials of Different Agents Cannot Be Compared Directly Vertebral Fracture Effects In rospective Trials Direct Comparisons Among Trials Cannot Be Made Effect on fracture risk Agent Spine on-spine Hip Alendronate Risedronate Ibandronate + - Zoledronic acid documented in a randomized, controlled trial; effect not documented effect documented only in a post hoc analysis of a high-risk sub-group (femoral neck T score < -3) and in a meta-analysis of clinical trials (Harris ST, et al. Curr Med Res pin 28;24:237-24) % of atients With ew Vertebral Fractures ver 3- Years % Calcium CT RLX AL RIS IB ZL 3% 47% RF MRE FIT-VFA VERT-A VERT-M BE HRIZ MRE FIT-CFA With revalent Vertebral Fractures ± Vert Fx Chesnut CH, et al. Am J Med. 2;19:267 Ettinger B, et al. JAMA. 1999;282:637 Black DM, et al. Lancet. 1996;348:13 Cummings SR, et al. JAMA. 1998;28:277 Harris ST, et al. JAMA. 1999;282:1344 Reginster J, et al. steoporos Int. 2;11:83 Chesnut CH, et al. J Bone Miner Res. 24;19:1241 Black DM, et al. Engl J Med 27:36:189 41% 49% % Relative Fracture Risk Reduction 2% 7% % % Without Vert Fx % of atients With ew onvertebral Fractures ver 3- Years onvertebral Fracture Effects In rospective Trials Direct Comparisons Among Trials Cannot Be Made * % p n.s. Calcium CT RLX AL RIS IB ZL 1% p n.s. 2% p.6 12% p n.s. % Relative Fracture Risk Reduction 39% p <. 33% p.6 p n.s. 2% p <.1 RF MRE FIT-VFA FIT-CFA VERT-A VERT-M BE HRIZ Fracture Endpoints h If existing randomized clinical trials cannot address all issues of clinical relevance, then additional insights can be gathered from: ost hoc analyses of existing trial data Meta analyses of existing trial data bservational data Chesnut CH, et al. Am J Med. 2;19:267 Ettinger B, et al. JAMA. 1999;282:637 Black DM, et al. Lancet. 1996;348:13 Cummings SR, et al. JAMA. 1998;28:277 Harris ST, et al. JAMA. 1999;282:1344 Reginster J, et al. steoporos Int. 2;11:83 Chesnut CH, et al. J Bone Miner Res. 24;19:1241 Black DM, et al. Engl J Med 27:36:189 * atient demographics and the definition of nonvertebral fracture varied among studies

5 Fracture incidence (%) Monthly Ibandronate vs Weekly Bisphosphonates at 12 Months 1.6 RR.88 p Fx738 Fx9 Monthly oral ibandronate (n7,34) Weekly oral Bs (n6,837) RR1.6 p.84 Fx1 RR.36 p< Fx16 RR.82 p.2 RR adjusted RR (hazard ratio) using Cox regression controlling for potential confounders Fx13 Fx88 Fx13 on-vertebral Hip Vertebral Any Fractures Fx Bisphosphonate Trials: Summary hwe have available for use four -containing bisphosphonates, all of which share a common mechanism of action h There are pharmacokinetic differences among the bisphosphonates, but the clinical implications of those differences are not firmly established hthe induced changes in BMD with the four bisphosphonates may be subtly different, but all reduce fracture to a greater extent than one would predict from the change in BMD alone; i.e., they all improve bone quality Harris ST, et al. Bone 29;44:78-76 Bisphosphonate Trials: Summary, con t steoporosis: Extended Therapy? hit is possible to compare the pivotal trials of different treatment agents vis-à-vis fracture endpoints but it is much more difficult to draw firm clinical conclusions from those comparisons hthe pivotal trials studied similar populations of postmenopausal women, but there were nevertheless important differences in demographics, inclusion criteria and fracture endpoints h Absence of evidence is not evidence of absence h The safety record of contemporary treatment agents is excellent, but there is a remaining concern about potential long-term skeletal toxicity, particularly with long-lived agents such as the bisphosphonates h It s not clear if treatment should be continued indefinitely, interrupted with a drug holiday, or terminated

6 Bisphosphonate Therapy h Bone biopsies after years of risedronate therapy 1 and 1 years of alendronate therapy 2 have shown no histologic abnormalities h Fracture rates remain low after 7 years of risedronate therapy 3 and 1 years of alendronate therapy 4, 1. Ste-Marie LG, et al. Calcif Tissue Int. 24;7: Recker RR, et al. J Bone Miner Res. 24;19(suppl 1):S4 3. Mellstrom DD, et al. Calcif Tissue Int. 24;7: Bone HG, et al. Engl J Med. 24;3:1189. Black DM, et al. Engl J Med 27;36:189 Incidence per year (%) Vertebral Fractures ver 7 Years of Risedronate Therapy VERT-M: Radiographic Vertebral Fracture* Years -3 Years 4- Subjects switched to risedronate mg at end of year lacebo Ris mg lacebo Ris mg Ris mg Ris mg Years 6-7 *Annualized fracture incidence represents the percentage of patients experiencing any new vertebral fracture divided by the number of years in the observed interval. FIT Long-Term Extension (FLEX) h Women previously on alendronate for 3-6 years were randomly assigned to years of alendronate ( or 1 mg daily) or placebo h Alendronate vs placebo Clinical spine fracture: RR.4 (.23,.84) Morphometric spine fracture: RR.87 (.61, 1.2) onspine fracture: RR1. (.76, 1.32) Black DM, et al. JAMA 26;296: Mean ercent Change From FIT Baseline, % FLEX: % Change in Spine BMD FIT 3 to 4. years F F 1 F 2 F 3 F 4 FL FL 1 FL 2 FL 3 FL 4 FL AL/lacebo (n 437) AL/AL (pooled -mg and 1-mg groups: n662) Black DM, et al. JAMA 26;296: Time Between FIT and FLEX 1 to 2 years Year FLEX years 3.7% <.1

7 Mean ercent Change From FIT Baseline, % FLEX: % Change in Femoral eck BMD FIT 3 to 4. years F F 1 F 2 F 3 F 4 FL FL 1 FL 2 FL 3 FL 4 FL AL/lacebo (n 437) AL/AL (pooled -mg and 1-mg groups: n662) Black DM, et al. JAMA 26;296: Time Between FIT and FLEX 1 to 2 years Year FLEX years 1.9% <.1 Fracture Incidence, % FLEX: Incidence of Fractures Relative Risk Reduction % ARR 2.9%.13 RR.4 CI (.2,.8) AL/LB (n 437) AL/AL (n 662) RR.9 CI (.6, 1.2) RR 1. CI (.8, 1.4).3% 2.4% 11.3% 9.8% 19.% 18.9% Clinical Vertebral Vertebral Morphometric on-vertebral Black DM, et al. JAMA 26;296: FLEX Summary and Conclusions h ver 1 years (FIT and FLEX), continuous alendronate treatment: revented bone loss at the total hip and increased BMD at the femoral neck and lumbar spine Maintained biochemical markers of bone turnover at levels similar to FLEX baseline Reduced the relative risk of clinical vertebral fracture by % (ARR 2.9%) Resulted in normal bone histology h Discontinuation of alendronate treatment in FLEX: Resulted in a loss of total hip and femoral neck BMD Led to a rise in biochemical markers of bone turnover Resulted in more clinical vertebral fractures but had no effect on morphometric vertebral fractures or non-vertebral fractures in the entire study group Black DM, et al. JAMA 26;296: FLEX: VF Risk with Extended Alendronate Therapy Stratified by Baseline Femoral eck BMD 199 patients enrolled in FLEX 723 with no vertebral fracture at FLEX baseline Baseline F BMD Risk Difference Relative Risk T-score > % 1.41 (.7, 2.66) T-score %. (.26,.96) Schwartz AV, et al. Efficacy of continued alendronate for fractures in women without prevalent vertebral fracture: The FLEX Trial. ASMBR 29 th Annual Meeting, resentation 17

8 Bisphosphonates: Side Effects h Class warning regarding UGI symptoms (no increase in UGI complaints in randomized controlled trials) h Class warning regarding infrequent bone, joint and/or muscle pain h Class warning regarding jaw osteonecrosis hinfluenza-like symptoms may occur after first monthly oral dose or IV injection steonecrosis f The Jaw (J) h An area of exposed alveolar or palatal bone that typically shows poor healing over several months. rior to bisphosphonate use, J was described in HIV and in osteopetrosis. ow associated uncommonly with high dose, chronic IV bisphosphonate treatment of myeloma and cancer metastatic to bone (9% of reported cases) 1 ain in 2/3 of cases: infection may or may not be present. Known risk factors: invasive dental procedures (tooth extraction or implants), oral trauma, periodontitis, poor oral hygiene, radiotherapy to the jaw, chemotherapy, corticosteroids, infection athogenesis is not known 2 1 Woo SB, et al. Ann Intern Med. 26;144:73 2 Khosla S, et al. J Bone Miner Res. 27;22: steonecrosis f The Jaw In atients Taking Bisphosphonates For steoporosis hj reported rarely in patients taking oral bisphosphonates for osteoporosis or aget s disease of bone 1 ho reports of J in controlled clinical trials (most of 2-3 years duration) involving 6, patient years of exposure to oral bisphosphonate therapy for osteoporosis 2 Includes over 3,88 patients in long-term trials of 3-1 years of continuous bisphosphonate use htwo cases of J in zoledronic acid osteoporosis trial 1 in the placebo group and 1 in the zoledronic acid group 3 1 Woo SB, et al. Ann Intern Med. 26;144:73 2 Khosla S, et al. J Bone Miner Res. 27;22: Black DM, et al. Engl J Med. 27;36:189 Bisphosphonate-Related J: Incidence The Background Incidence in the General opulation is ot Known Underlying Malignancy steoporosis aget s Disease IV 1% to 1% Rate not published Rate not published Khosla S, et al. J Bone Miner Res 27;22; /1, to <1/1, patient-treatment-years

9 J recautions And Management * hatients beginning a bisphosphonate for osteoporosis Ensure that patient is in a regular program of oral hygiene. If not, program should begin. Ideally, invasive procedures should be completed prior to bisphosphonate therapy, if possible hatients on bisphosphonates for osteoporosis Routine dental care (cleaning, hygiene, filings, etc) as recommended for the general population without the need to interrupt bisphosphonate therapy Dental surgery (extractions, implants, etc) should be limited to that required for good dental health and only when more conservative approaches are either not indicated or not effective h o data available to suggest whether temporary discontinuation of bisphosphonate treatment during dental treatment reduces J risk hatients with complaints referable to the oral mucosa or to underlying bone should be referred to a dentist or oral surgeon Atrial Fibrillation: FDA Review Updated 28 h n ctober 1, 27, FDA announced that it was reviewing safety data that raised concerns about a potential increased risk for atrial fibrillation in patients treated with a bisphosphonate drug. An article and an accompanying letter to the editor in the May 3, 27, issue of The ew England Journal of Medicine described increased rates of serious atrial fibrillation in two different studies of women ages 6 to 89 years old with osteoporosis treated with the bisphosphonates, Reclast and Fosamax After our review, based on the data available at this time, healthcare professionals should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their bisphosphonate medication. h n ctober 1, 27, FDA began requesting placebo-controlled clinical trial information from the sponsors of alendronate, ibandronate, risedronate, and zoledronic acid in order to explore the potential risk for atrial fibrillation in male and female patients treated with these bisphosphonate drugs. The data submitted by the four sponsors included data on 19,687 bisphosphonate-treated patients and 18,38 placebo-treated patients who werefollowed for 6 months to 3 years. h The occurrence of atrial fibrillation was rare within each study, with most studies containing 2 or fewer events. The absolute difference in event rates between each of the bisphosphonate and placebo arms varied from -3 per 1,. h ne large study of zoledronic acid showed a statistically significant increase in the rate of serious atrial fibrillation events. However, across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious atrial fibrillation was observed. Increasing dose or duration of bisphosphonate therapy was also not associated with an increasedrate of atrial fibrillation. * Adapted from Council on Scientific Affairs of American Dental Assoc Atypical Fractures There has been a theoretical concern that oversuppression of bone remodeling could impair the repair of microdamage and increase the risk of atypical fractures There are several small series of cases: - often fractures of femoral diaphysis - transverse rather than spiral fracture - often on other drugs, especially steroids or estrogen - some with stress reaction or stress fracture and prodromal pain syndrome There is no consensus about the frequency with which these atypical fractures might occur 1. Goh S-K, et al. J Bone Joint Surg Br. 27;89: Imai K, et al. J Bone Miner Metab. 27;2: eviaser AS, et al. J rthop Trauma. 28;22: dvina C, et al. J Clin Endo Metab. 2;9: Bisphosphonate Therapy h Long-term treatment has not clearly been associated with safety issues or loss of efficacy h In high-risk patients, continued treatment seems reasonable; there is no mandate to stop treatment h Cessation of treatment after 2- years is associated with some persisting effect on biochemical markers, as well as BMD; this has been best characterized for alendronate h The limited available data suggest a persisting effect on fracture risk; this has again been best characterized for alendronate