AN OVERVIEW of TREATMENT: WHO and WHEN to TREAT

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1 AN OVERVIEW of TREATMENT: WHO and WHEN to TREAT Dolores Shoback, MD Professor of Medicine, UCSF San Francisco VA Medical Center July 16, 21 ~ QUESTIONS ~ Who should receive therapy to prevent fractures? What is the efficacy of approved therapies and how do you select the best therapy for the patient? How do you manage patients at risk for bone loss? What is the (optimal/safe) duration of therapy? How long should a drug holiday be? Disclosures: Speaker Novartis; Consultant Amgen ~ QUESTIONS ~ Who should receive therapy to prevent fractures? FRAX NOF Guidelines Clinician s Guide (28,29) FRAX: Calculating 1-Year Fracture Probability What is the efficacy of approved therapies and how do you select the best therapy for the patient? How do you manage patients at risk for bone loss? What is the (optimal/safe) duration of therapy? How long should a drug holiday be? FRAX web site at: 1

2 FRAX Issues (Watts et al, JBMR, 29) Ethnicity is incorporated in US version (white, black, Asian, Hispanic) Men are included (both screening & treatment) Risk factors in FRAX - well-chosen & validated - BUT - not all inclusive ONLY aspect of family history is parental HIP FRACTURE Steroid use: prednisolone 5 mg/d or more for 3 mos or more (now or in past) FRAX Issues (Watts et al, JBMR, 29) SILENT on vitamin D status Propensity for falls, exercise habits - not incorporated Bone markers - not used Previous treatment - disqualifies patient from FRAX use (treatment-naïve pts only) Other bone-active drugs - not considered Multiple secondary risk factors - not counted Multiple fractures - not counted Spine BMD - ignored Dose/duration - smoking, alcohol - not counted More refinements are coming/needed Despite good intentions not being used Patients need help with weighing risks * NOF - Clinician s Guide to Prevention and Treatment of Osteoporosis (28) 13 New Recommendations: Postmenopausal Women and Men over 5... (3) Assure adequate intakes of Ca (at least 12 mg/d) & vitamin D3 (8 to 1 IU/d) (6) Do BMD testing -- women > 65 & men > 7 (7) Postmenopausal women (< 65) & men 5-7, obtain BMD if there is concern - based on risk profile NOF - Clinician s Guide to Prevention and Treatment of Osteoporosis (28) (cont d) (9) Start therapy in pts with hip or vertebral (clinical or morphometric) fractures **** (1) Initiate therapy if BMD T-score < -2.5 at fem neck, total hip or spine by DXA (11) Treat postmenopausal women & men aged 5 or > w/low bone mass (T-score -1 to -2.5 OSTEOPENIA) at fem neck, hip, spine & 1 yr hip fx probability > 3% or 1 yr major osteoporosis-related fx probability of > 2% 2

3 ~ QUESTIONS ~ Who should receive therapy to prevent fractures? What is the efficacy of approved therapies and how do you select the best therapy for the patient? How do you manage patients at risk for bone loss? What is the (optimal/safe) duration of therapy? How long should a drug holiday be? Fracture Reduction Spine Hip Non-vert ET/HT XX XX Calcitonin XX Raloxifene XX Alendronate XX XX XX Risedronate XX XX XX Ibandronate XX X Zoledronic Acid XX XX XX Denosumab XX XX XX Teriparatide XX XX Drug Selection in the Individual Patient What efficacy trying to achieve Adverse event profile of the agent (vs patient) Patient acceptance Osteoporosis Drugs: AE s, Contraindications & Considerations PO bisphosphonates esophageal irritation & ulceration, GERD, joint pains; avoid in pts with GFR < 35 ml/min (can t use) IV bisphosphonates flu-like symptoms (esp 1st dose), need to be sure pt is vitamin D replete, must be well-hydrated at time of infusion avoid if borderline renal dysfunction (extreme care) ** PREFER IV bisphosphonate in the post-hip fracture patient (i.e., zol acid) 3

4 Zoledronic Acid after Hip Fractures: Mortality & Recurrent Fractures RCT evaluated yearly IV ZOLEDRONIC ACID 5 mg to prevent fractures & decrease mortality in pts with hip fx Enrolled within 9 days from surgical repair of hip fx Placebo: 162 pts 26 MEN (24.5%) Zoledronic acid: 165 pts 248 MEN (23.3%) Zoledronic Acid after Hip Fractures: Mortality & Recurrent Fractures HAZARD RATIOS Any clinical fracture.65 p =.1 Clinical nonvert fracture.73 p =.3 Clinical vert fracture.54 p =.2 Hip fracture.7 p NS DEATH ***.72 p =.1 **Especially high-risk population to treat Lyles K, et al. NEJM, 27 Lyles K, et al. NEJM, 27 Osteoporosis Drugs: AE s, Contraindications & Considerations Raloxifene hot flashes, venous TE; also approved for breast cancer prevention; NO hip fracture/nonvert efficacy HT/ET VTE, RR breast ca, CVD (depending on pt age); good fracture efficacy but NO pts wish to take it! Calcitonin nasal irritation; low efficacy (routine cases); avoid using in severe osteoporosis; can use in CKD pts but no efficacy data Osteoporosis Drugs: AE s, Contraindications & Considerations Teriparatide headaches, leg cramps, hypercalcemia; no published experience in pts with CKD/reduced GFR but avoid it in pts with secondary HPTH; costly ($$$) + daily injections; black box warning Denosumab PI indications - treatment of postmenopausal osteoporosis (NOT men as yet) at high risk for fracture = history of osteoporotic fracture or multiple risk factors for fracture or who have failed or are intolerant to other therapy 4

5 Indications for Teriparatide Glucocorticoid-induced osteoporosis with moderately low to severely low BMD and or fractures low turnover state teriparatide performs well Patients with severe osteoporosis T scores -3. to - 4. range or lower with (or without) fractures First-line therapy if possible Rebuild the scaffold of bone Patients intolerant to or failed other agents Had a fracture on therapy Treat men ~ same as women (less data) Warnings & Precautions: Denosumab Serious infections (incl skin infections - cellulitis) may occur Dermatologic reactions dermatitis, rashes, eczema Monitor for symptoms of ONJ Monitor for consequences of bone oversuppression NO dose adjustment with CKD Monitor for hypocalcemia and assure pt does not have hypocalcemia if renal impairment present ( and D deficiency) * ~ QUESTIONS ~ Who should receive therapy to prevent fractures? What is the efficacy of approved therapies and how do you select the best therapy for the patient? How do you manage patients at risk for bone loss? What is the (optimal/safe) duration of therapy? How long should a drug holiday be? Zoledronic Acid to Prevent Bone Loss: Women with Low BMD (McClung et al, Ob Gyn, 29) 581 women with osteopenic BMD (LS < -1. to > -2.5 and FN > -2.5) Age: 6 Treatment: placebo -or- zoledronic acid 5 mg X 1 -OR- 5 mg X 2 over 24 mos Ca 5-12 mg, vitamin D 4-8 IU 5

6 BMD mos 24 mos SPINE HIP HIP SPINE Bone Turnover Markers placebo zol 1x5 mg zol 2x5 mg -2 Placebo, 5 mg, 5 mg X2 zol acid All p <.1 vs baseline & placebo McClung et al, Ob Gyn, 29 McClung et al, Ob Gyn, 29 * ~ QUESTIONS ~ Who should receive therapy to prevent fractures? What is the efficacy of approved therapies and how do you select the best therapy for the patient? VERTEBRAL FRACTURES: VERT-MN Extension (Mellstrom et al, CTI, 24) 49% p<.1 59% p<.1 How do you manage patients at risk for bone loss? What is the (optimal/safe) duration of therapy? (5 years, 1 years, lifelong ) FX in this group did not go up How long should a drug holiday be? 6

7 RISEDRONATE: Safety 7 year data: No xs adverse events (focus - GI/esoph) BTM s -- pre-menopausal levels NO loss of anti-fracture efficacy (vert s) ~ SAME non-vert fx rate: 7.4% in plac/ris vs 6.% in RIS Mellstrom et al, CTI, 24 5 year bone biopsy data (N=12 pairs) NO pathologic findings Double tetracycline labels in all Osteoid vol 27% Mineralizing surface 49% Activation frequency 77% Ste-Marie et al, CTI, 24 Cumulative Incidence of Nonvert & Clinical Vert Fx s: FLEX Study Black, DM et al. JAMA 26;296: % 5 yrs ~ 1 yrs 1 yrs - BETTER FLEX Study: Safety Bone histomorphometry - double labels seen in all biopsies (N=18) No EXCESS fractures in women who took ALN for 1 yrs, fewer vert fractures Consider drug holiday in women after 5 yrs Post-hoc subgroup: consider carefully if hip BMD still 5 yr ~ QUESTIONS ~ Who should receive therapy to prevent fractures? What is the efficacy of approved therapies and how do you select the best therapy for the patient? How do you manage patients at risk for bone loss? What is the (optimal/safe) duration of therapy? How long should a drug holiday be? Must individualize Black et al, JAMA, 26; Colon-Emeric, JAMA, 26; JBMR 21 7

8 Risk of Hip Fracture during Drug Holiday (Curtis et al, Osteo Int, 28) Data from US health care org (>25 mill pts) Rate of hip FX in women who d/c BP -VSremained on therapy (2 or 3 yrs) - (not randomized) 6% ALN, 2% RIS, rest daily 6-78 yrs old MPR (medication possession ratio) Examined 2 & 3 yrs therapy & MPR < 5%, > 66%, 8-1% There was NO increase in hip FX rate (over 1 yr) if you d/c BP after - 2 yrs therapy if MPR > 8% - or - 3 yrs therapy if MPR > 66% There was an increased risk if less (exposure) Risk begins 1 yr after d/c * ~ CONCLUDING THOUGHTS ~ Aggressive treatment of pts at high risk for fracture Reasonable to use FRAX cut-points Add in clinical risk factors not captured by FRAX Pt who already have fractures need therapy Consider prevention of loss by safe strategies There are many effective therapies and eventually we will learn how to use them! 8

9 Anti-Resorptive Therapies Fracture Reduction (% vs placebo) -- Not H2H Oral Bisphosphonates Fracture Reduction (% vs placebo) -- Not H2H Spine Fractures Spine Fractures Vert Hip Total Spine Non- Vert Hip Spine Hip All clinical Spine Hip, Non- Non Vert Vert T< -3 * Hip Hip Nasal CT (5 yrs -PROOF) Raloxifene (4 yrs - MORE) HRT/ERT -WHI ( yrs) Risedronate (3-5 yrs: VERT, HIP) Alendronate (3-4 yrs: FIT) Ibandronate (3 yrs: BONE) IV Bisphosphonate/RANK-L Inhibitor Fracture Reduction (% vs placebo) Spine Hip Non- Vert Spine Hip Non Vert Teriparatide/PTH Reduces Fracture Risk % Reduction vs Placebo (Neer et al, NEJM, 21) 77%* 65%* 53%** 1 Zoledronic Acid (3 yrs: HORIZON) Denosumab (3 yrs: FREEDOM) *anti-resorptive *p<.1; ** p=.2 Vert s Mult Vert s Nonvert Hip 9

10 BISPHOSPHONATES: Long Term Studies Data from 1 yr continuation studies of daily ALN in women with osteoporosis (Phase III) Data from 7 yr study with risedronate in PMO (VERT) Data from 5 yr continuation of FIT with Aln (compared 5 vs 1 yrs of treatment) (FLEX) BMD Responses in PMO women/1 YRS: ALN 1 mg discontinuation 5 mg BTM not at baseline No diff/effect on FX Bone et al, NEJM, LUMBAR SPINE BMD: Risedronate vs Placebo (Mellstrom et al CTI, 24) BMD Changes in FLEX: Extension of FIT Study 12 1 Risedronate, 7 yrs 11.5% 8 % Base line Placebo, 5 yrs RIS, 2 yrs yrs 6.1% Black, DM et al. JAMA 26;296: * 1

11 SUMMARY Biochemical Markers of Bone Turnover in FLEX Comparable BMD effects - 1 vs 2 doses of zol acid over 2 yrs Durable BTM responses (24 mos w/1 dose) Adverse events (> vs placebo): pain (24%) chills (18%) pyrexia (22%) nausea (15%) myalgia (19%) fatigue (15%) No atrial fib, ONJ, long-term renal dysfunction Safe/effective strategy to preserve bone in this population Black, D. M. et al. JAMA 26;296: FLEX Study: Effects of Continuing or Stopping Alendronate (Black et al, JAMA, 26) Risk of Clinical Vertebral & Non-vertebral Fractures: Annual - 5 mg Zoledronic Acid IV 199 women taken ALN during FIT for ~ 5 yrs Randomized: ALN 5 or 1 mg or placebo X 5 more yrs 1 o outcome: total hip BMD 2 o outcome: other sites & biochemical markers Analyzed -- all fractures Did NOT randomize women with T scores of or < or BMD lower than at start of FIT (total hip) Placebo (n = 3861) Clinical Vertebral Fracture Months *RR reduction vs placebo P <.1 77%* (63%, 86%) ZOL 5 mg (n = 3875) Non-vertebral Fracture 25%* (13%, 36%) P < Months Black DM, et al. NEJM, 27 11

12 Cumulative Incidence (%) RR reduction (95% CI) vs placebo Black DM, et al. NEJM, 27 Cumulative Risk of Hip Fractures: Annual 5 mg Zoledronic Acid IV Placebo (n = 3861) ZOL 5 mg (n = 3875) P = Time to First Hip Fracture (months) 41%* (17%, 58%) CASE An endocrinologist from No Calif calls for a telephone consult 51 yo female ref by PCP for advice on further mgmt Fosamax for 5 yrs & Premarin for 1 yrs Multiple fractures: left patella left wrist (preventing a filing cabinet from falling) left ankle (minor fall) 25 - left hip (followed by THR) 25 - left femoral shaft fracture 29 - right hip fracture (after a trip followed by THR) 29 - right femur fracture Adopted - no family history Partial complex seizure disorder - Dilantin or Tegretol X > 2 yrs TAH, BSO in 2 given premarin thereafter 25 DXA: CASE Total hip T score: Femoral neck T score: L spine: +.75 (osteophytes) Can t get any more DXA s (d/t THR s) 25 OH D = 39, labs are OK HIS QUESTIONS. CASE Should I stop the Alendronate and or the Premarin? Should I start Teriparatide? Are there any new therapies she d be eligible for? Should she be evaluated for osteogenesis imperfecta - her sclerae look blue? Why so many fractures - are these - atypical fractures? 12

13 Safety Issues - Bisphosphonates - 1 Renal Transient rises in S-creat esp w/iv BP s; generally NO cumulative impact on renal fct; use if egfr > 35 Cardiac Increased risk of afib as serious AE (w/zol acid) FDA review of atrial fibrillation (28) 19,687 BP-treated pts + 18,358 controls (followed 6 mos - 3 years) - IBN, RIS, ALN, Zol -- NO clear association between AFib and BPs Prescribers should NOT alter prescribing patterns for BP s Cohort Study - Hospital-treated Fractures Matched to Controls ( ) Abrahamsen et al, JBMR, 29 13