HRT and Risedronate Combined Anabolic and Antiresorptive Therapy

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1 Optimizing Combined and Sequential Osteoanabolic and Antiresorptive Therapy Benjamin Leder, M.D. Endocrine Unit Massachusetts General Hospital Boston, MA Antiresorptive and Osteoanabolic Therapies Increase BMD modestly Reduce vertebral fractures in high risk populations Reduce non-vertebral fractures modestly in high risk populations Are unable to restore skeletal integrity in most patients with established disease Di s c l o s u re s Amgen (c ons ulting, res earc h funding) Lilly (consulting, research funding) Me rc k (c o n s u l t i n g ) Anti-remodeling and Osteoanabolic Therapies Combination Therapy mechanism of action esor ptive Alendronate antir - bisphosph o na te Zoledr onic acid antir esor ptive - bisphosph o na te Denosumab antir esor ptive - RANKL-inhibit or Ter ipar atide anabolic- PTH analog -yr incr ease -yr incr ease RRR of RRR of nonspine spine BMD total hip BMD spine fx fx 5% 3% 53% % 5-% 3-% 7% 5% -% 3-% % % -1% 1.5-% 5% 35% Osteoporosis is one of the few chronic conditions for which there is no accepted role for using more than one drug at a time. Approaches to combination therapy: Combination anti-remodeling therapy Blac k et al. Lancet. 199;3(91): Blac k et al. N Engl J Med. 7;35(1):19-1. Cummings et al. N Engl J Med. 9;31( ): Neer et al. N Engl J Med. 1;3(19): Anti-remodeling drug plus anabolic HRT and Risedronate Combined Anabolic and Antiresorptive Therapy Double blind, placebo-controlled study of 5 postmenopausal women (mean age ). Treatment for 1 with: Teriparatide: bone resorption and bone formation Bisphosphonates: bone resorption and bone formation conjugated equine estrogens (.5 mg) HRT plus risedronate (5 mg). Fem or al Neck Can osteoblast and osteoclast function be unlinked? bone formation and bone resorption Harris et al. JCEM 1

2 Parathyroid Hormone Anabolic Activity Multiple target cells and potential mechanisms of action remodeling based bone formation Parathyroid Hormone Anabolic Activity Multiple target cells and potential mechanisms of action modeling based bone formation PTH activation of lining cells PTH mature osteoblasts mature osteoblasts pre-osteoblast pre-osteoblast osteoclasts Martin et al, JBM 1 inhibition of apoptosis osteoclasts Martin et al, JBM 1 accelerated remodeling osteocytes osteocytes decr eased scler ostin PTH plus Alendronate: PATH Study PTH plus Alendronate: PATH Study P1NP CTX 3 women with PMO. Spine Randomized to alendronate 1 mg/day, hpth-(1-) 1 ug/day, or both for 1 in BMD Black et al NEJM 3 1 treatment -naïve women with PMO. 1-year RCT. Zoledronic Acid plus Teriparatide Spine Fem Neck Why are Combined PTH + Bisphosphonates Not Additive? Resorption is required for PTH s anabolic effects more potent antiresorptive = combo less effective Treatment Groups: zoledronic acid teriparatide combination CTX TPTD Both P1NP TPTD Both Bisphosphonates do not fully block PTH-induced bone resorption. more potent antiresorptive = combo more effective ZA ZA Cosman et al JBMR 1

3 Denosumab PTH and Resorption-Independent Anabolism Mechanism of action Antiresorptive potency Male RANK / osteopetrotic mice and WT littermates ( wk) Eroded Surface (ES/BS, %) ALN treated for 1 days: (Kostenuik et al, JBC 11) PTH mcg/kg/day sc daily Vehicle daily Reid et al. JBMR 1 Denosumab And Teriparatide Administration Studies (DATA) Inclusions Exclusions DATA Studies DATA DATA-Switch DATA-Follow-up women aged years no menses. BMD: <-.5 at any anatomic site, or- <- with 1+ risk factor, or- <-1 with a history of fragility fracture. 5-OH vitamin D < ng/ml. oral bisphosphonates in the past. estrogens, SERMS, or calcitonin in past 3. any prior teriparaide, IV bisphosphonates, denosumab. Combination (n=3) 1-3 m onths No Treatment VS Treatment Tsai et al. Lancet 13, Leder et al. JCEM 1 Final DXA DATA Study Subjects Teriparatide (n=31) Denosumab (n=33) Combination (n=3) Age Denosumab And Teriparatide Administration Study (DATA) DATA DATA-Switch DATA-Follow-up BMI (kg/m ) Previous oral bisphosph on at e use % 3% 33% Duration of oral bisphosphonat e use (m onths) Tim e since last or al bisphosph o na te usage (m onths) Combination (n=3) 1-3 m onths No Treatment VS Treatment Final DXA 5-OH Vitamin D (ng/ml) Fem Neck BMD (g/cm ) Total Hip BMD (g/cm ) Spine BMD (g/cm ) Tsai et al. Lancet 13, Leder et al. JCEM 1

4 1 1 1 BMD BMD 1 1 Total Hip BMD Total Hip BMD Femoral Neck BMD Femoral Neck BMD

5 1/3 Distal Radius BMD Comparisons to Bisphosphonates (1 Year) - Spine BMD 1 TPTD Both 1 PTH ALN Both TPTD ZA Both Fem Neck BMD TPTD Both TPTD ZA Both PTH ALN Both DATA Study Zoledr onic Acid S tudy PATH Study Cosman et al. JBMR 11 Black et al. NEJM 3 Bone Resorption (CTX) Bone Formation (Osteocalcin) month change month change month change month change 3 month change month change Tsai et al. Lancet 13 Tsai et al. Lancet 13 Bone Formation - Osteoblast Activity Osteocalcin Bone Resorption Comparisons to Bisphosphonates Combinations after 1 Year P< P<.1 P=.9 P=. P=.11 BOTH Month! Zoledronic Acid Study Cosman et al. JBMR 11! DATA Study

6 HR-pQCT Features Normal Bone µm pixel size allows for the visualization of the 3D trabecular network (distal tibia and radius), Measurments appear to correlate with fracture even after accounting for BMD Total Volumetric BMD Osteoporosis Cortical Volumetric BMD Cortical Thickness Cortical Porosity Estimated Strength (FEA) Failure Load TPTD BOTH P<.5 versus TPTD

7 Combination Therapy Summary Combination Therapy Summary Compared to monotherapy, and unlike bisphosphonate-containing combinations, combined denosumab + teriparatide: increases spine and hip BMD Improves peripheral cortical microarchitecture and strength Alendronate -month changes in BMD Mechanism Spine Total Hip antir esor ptivebisphosphonate 5% 3% The mechanisms underlying the effects of combined denosumab and teriparatide need to be defined: Denosumab s ability to fully block teriparatide s proresorptive effects Continued modeling-based bone formation (uncoupling) Zoledr onic acid Denosumab antir esor ptivebisphosphonate antir esor ptive-ranklinhibitor 5-% 3-% -% 3-% Given denosumab s antiresorptive potency, more extensive uncoupling may be possible using a stronger anabolic. Ter ipar atide anabolic- PTH analog -9% 1.5-% Combination denosumab + ter ipar atide 1.7%.3% Sequential Osteoporosis Treatment In contrast to bisphosphonates, when denosumab or teriparatide are discontinued, BMD gains are rapidly lost. Denosumab And Teriparatide Administration Study (DATA-Switch) DATA DATA-Switch DATA-Follow-up Effect of this rapid bone loss on fracture risk is unknown. The use of bisphosphonates after teriparatide is associated with BMD increases similar to de novo treatment. Combination (n=3) 1-3 m onths No Treatment VS Treatment Final DXA The use of teriparatide after bisphosphonates is associated with blunted BMD response at the spine. Tsai et al. Lancet 13, Leder et al. JCEM 1 TPTD TPTD 15 TPTD

8 Femoral Neck TPTD 1 TPTD 15 TPTD TPTD Femoral Neck Femoral Neck 1 TPTD 1 TPTD TPTD Total Hip Total Hip 1 TPTD 1 TPTD TPTD

9 Total Hip Distal Radius 1 TPTD TPTD - TPTD TPTD Distal Radius Distal Radius TPTD TPTD TPTD Bone Turnover Consequences of Short-Term Accelerated Turnover Osteocalcin C-telopeptide TPTD TPTD 3 1 TPTD TPTD TPTD TPTD TPTD TPTD TPTD TPTD

10 Consequences of Short-Term Accelerated Turnover Sequential Therapy Summary In postmenopausal osteoporosis, the order in which denosumab and teriparatide are used has a significant impact on overall treatment efficacy. postmenopausal experienced 11 fractures. Mean number of fractures per patient =.7. All fractures occurred -1 after last denosumab injection. 9% of patients had >1 vertebral fracture Using teriparatide after denosumab is associated with transient or sustained bone loss. Using denosumab after teriparatide further increases BMD at the spine and hip and maintains BMD at peripheral cortical skeletal sites. Sequential Therapy Summary Largest -year BMD gains among patients treated with combination therapy followed by denosumab: Year s Alendronate Year s Zoledr onic Acid -Years Denosumab Year s Com bination Ther apy + years Denosumab alone Spine -9% 1% 11% 1% Denosumab And Teriparatide Administration Study (DATA-follow-up) Ter ipar atide Denosumab Combination (n=33) (n=31) (n=3) Denosumab Ter ipar atide Denosumab (n=31) (n=33) (n=31) 1-3 m onths No Treatment VS Treatment Final DXA Total Hip 3-% 5% 5-%.% Leder et al. Bone 17 Black et al. JBMR 1, Black et al. JAMA, Papapoulos et al. JBMR 1. Denosumab And Teriparatide Administration Study (DATA-follow-up) Percent change in BMD between DATA-Switch Completion and Follow-up DXA DATA Follow-up Percent change in BMD Follow-up ther apy (n=) No follow-up ther apy (n=3) 1 ± 5 15 ± Time between DATA and follow-up DXA Tim e between DATA and tr eatm ent ± 3 (-11 r ange) Post-DATA treatment SC denosumab (number) 1 IV zoledronic acid (number) Oral ibandronate (number ) Oral alendronate (number ) Fractures in follow-up period 1 (tibia stress) 1 (patella) -5-1 Spine Fem Neck Neck Total Hip -5-5 Leder et al. ASBMR 1 Leder et al. Bone 17

11 DATA Follow-up DATA Follow-up Degree of bone loss in patients not receiving any follow-up therapy BMD changes in patients receiving follow-up therapy Leder et al. ASBMR 1 Leder et al. ASBMR 1 Conclusions Unlike bisphosphonate + teriparatide combinations, combined denosumab + teriparatide shows potential as a treatment strategy in patients at high risk of fragility fracture. The initial use of anabolic (or combo) therapy, followed by a potent antiresorptive, appears to be the most effective sequential approach in the treatment of PMO. Additional trials are needed to unequivocally demonstrate the efficacy and cost-effectiveness of these types of intensive osteoporosis treatment regimens. Fracture efficacy? Conclusions Length of combination anti-remodeling and anabolic therapy? Synchronized or staggered initiation of combination therapy? Use of higher dose or next generation anabolic agents? Acknowledgements Joy Tsai, MD Bob Neer, MD Sherri-Ann Burnett- Bowie, MD Alex Uihlein, MD John Potts, MD Liz McKay Ruchit Kumbhani Erica Siwila- Sackman Paul Wallace Linda Jiang