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Osteoporosis Update: Advances in Treatment Suzanne Jan de Beur, MD Johns Hopkins University School of Medicine 8/21/2021 1
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Incidentally Discovered Vertebral Fracture A 70 year old female smoker being evaluated for a cough presents for discussion of recently order chest xray. You explain that the CXR shows no infiltrates or masses in the lung tissue itself but there is an incidental vertebral compression fracture at T12 noted. 8/21/2021 2
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What do you ask next? 8/21/2021 3
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Delving Deeper Upon further discussion you ascertain: She remembers a 2 month history of significant back pain that spontaneously resolved after a fall from standing height while working in the yard 3 years ago shortly after she retired She is 2 inches shorter than her peak adult height No previous fractures 8/21/2021 4
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Delving Deeper: Secondary Causes No current or past history use of steroids Alcohol intake is one glass of wine daily 50 pack year history of smoking Menopause age 52 No weight gain or weight loss No diarrhea or malabsorption symptoms Physically active and rarely falls Normal renal function with no kidney stones 8/21/2021 5
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Medical History PMH: Hypertension Hyperlipidemia Medications: amlodipine 5 mg, simvastatin 20 mg, multiple vitamin for “seniors” SH: retired school teacher FH: no hip fractures in either parent, mother developed Dowager’s hump 8/21/2021 6
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Physical Exam P=75, BP=135/80, Wt: 150 lbs, Ht: 66 inches, BMI=24.2 No Cushing Features No kyphosis or pain on spinal palpation No goiter, tremor, thyroid eye finds 8/21/2021 7
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What next? 8/21/2021 8
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Laboratory and Imaging DXA Lumbar Spine Tscore -1.6 Femoral Neck T score -1.5 Total Hip Tscore -1.3 FRAX 10 year Probability MOF 16%, HF 3.7% Secondary Evaluation is normal CMP, phos, CBC, TSH, 24hr urine calcium/creatinine, 25D, PTH, SPEP/UPEP 8/21/2021 9
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What do you Advise? Counsel for smoking cessation Treat with appropriate calcium and vitamin D Counsel about Fall prevention A. Initiate treatment with pharmacotherapy OR B. Reassure the patient that no intervention is needed 8/21/2021 10
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Smoking Cessation Reduces Fracture Risk FRAX 10 year Probability MOF 16%, HF 3.7% No Smoking: FRAX 10 year Probability MOF 16%, HF 2.2% 8/21/2021 11
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Fracture is SKELETAL FAILURE 8/21/2021 12
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Fracture is a Powerful Risk Factor for Future Fracture Relative Risk Thinness 1.3 If BMI <21 Smoking 1.5 If current Family history 1.6 Sister of hip fracture 1.3 Mother Spine Non-Spine Fractures Non-spine 2.2 1.5 Spine 1 fracture 3.2 1.6 2 fractures 8.0 2.0
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Mortality Following Clinical Fractures Fracture Intervention Trial Cauley JA, et al. Osteoporos Int. 2000;11:556-561 *6459 postmenopausal women ages 55-81 years,followed for an average of 3.8 years Any Symptomatic Age-Adjusted Relative Risk (95% CI) 0.0 1.0 2.0 5.0 16.0 Non-spine Other Forearm Spine Hip 10.0 6.7 8.6
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Outcomes of Hip Fractures 300,000 hip fractures annually1 24% excess mortality in 12 months2 50% do not recover baseline function3 25% require long-term nursing home care4 1 U.S. Congress, OTA,. Hip Fracture Outcomes. OTA-BP-H-120, 1994. 2 Ray, N.F. et al. J. Bone Mineral Res. 1997;12:24-35 3 Consensus Develop. Conf., Am. J. Med. 1993;94:646-650 4 Riggs, B.J. and Melton, L.J. Bone 1995;17:505S-511S
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Guidelines for Osteoporosis Screening 8/21/2021 16
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Indication for Pharmacologic Treatment Initiate pharmacologic treatment in: Those with clinical or asymptomatic hip or vertebral fracture Those with a T score <-2.5 at the hip, spine or femoral neck Those with osteopenia and a FRAX 10 yr probability >20% of major osteoporotic fracture or >3% of hip fracture 8/21/2021 17
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Take Home Points A fragility fracture is skeletal failure Initiate pharmacologic treatment in: Those with clinical or asymptomatic hip or vertebral fracture regardless of T score Those with a T score <-2.5 at the hip, spine or femoral neck Those with osteopenia and a FRAX 10 yr probability >20% of major osteoporotic fracture or >3% of hip fracture 8/21/2021 18
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Advances in Treatment 8/21/2021 19
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Outline New long term data for Denosumab New data about treatment of Osteopenia New treatments: Abaloparatide New treatments: Romosozumab 8/21/2021 20
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2–4 weeks 3–4 months Resting stage Reversal phase Formation Remodeling completed Activation Resorption Lining cells Osteoclast precursors Osteoclasts Osteoblasts Bone remodeling unit Lining cells Normal Bone Remodeling
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FDA-Approved Osteoporosis Medications Antiresorptives Estrogen/HRT* Bisphosphonates Alendronate (Fosamax)* Risedronate (Actonel)* Ibandronate (Boniva) Zoledronic Acid (Reclast)* SERMS: Raloxifene (Evista) Bazedoxifene (Duavee) Calcitonin (Miacalcin) Denosumab(Prolia)* Anabolics Parathyroid Hormone (Teriparatide, Forteo) PTHrP Analogue (Abalopartide, Tymlos)* Romosozumab(Evenity) *reduces non vertebral fracture
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Denosumab New Long Term Data 8/21/2021 24
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Denosumab Mechanism 8/21/2021 25
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FREEDOM Extension 8/21/2021 26
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FREEDOM EXTENSION: 10 yr Data 8/21/2021 27 HM Bone, Lancet Diab Endo, 2017
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Incidence of New Fractures in Long Term Group 8/21/2021 HM Bone, Lancet Diab Endo, 2017 28
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FREEDOM EXTENTION 10 year data The FREEDOM trial open-label extension 4,450 women on denosumab for either 7 or 10 years 10 yrs of DMAb was associated with: sustained low fracture rates steadily increasing bone mineral density persistent reduction of bone turnover no increase in adverse events over time 8/21/2021 29
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Bone Markers Rebound within 3 months of Stopping Dmab 8/21/2021 Tsourdis, BONE, 2017 30
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Bone Density Drops within 6 months of Stopping Dmab 8/21/2021 Tsourdis, BONE, 2017 31
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Vertebral Fractures Increase when Dmab is Stopped 8/21/2021 32 ALL With Prevalent Vertebral Fracture Cummings, JBMR, 2018
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Take Home Points Denosumab must be administered in a timely and continuous fashion No medication holiday with denosumab Best practice for transitioning off treatment is being studied 8/21/2021 33
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Treatment Efficacy in Osteopenia 8/21/2021 34
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Zoledronic Acid in Women with Osteopenia IR Reid, NEJM, 2018 6 year, double-blind, placebo controlled trial 2000 women, age 65+ Osteopenia (T score -1 to -2.5 in the total hip/femoral neck) Zoledronic acid 5 mg every 18 months (4 infusions) OR Placebo Vitamin D administered and 1 gram calcium intake encouraged Primary endpoint: time to first occurrence of a fracture 8/21/2021 35
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Study Design and Baseline Characteristics 8/21/2021 36
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Zoledronic Acid in Osteopenia: Fracture Outcomes 8/21/2021 37
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Zoledronic Acid in Osteopenia: Fracture Outcomes 8/21/2021 38
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Adverse Events 8/21/2021 39
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Bisphosphonates and Mortality RCT of ZA in men and women after hip fracture demonstrated a 28% decrease in mortality (Lyles K, NEJM, 2007) Meta-analysis of 8 osteoporosis trials with duration >12 months showed a 11% reduction in mortality (Bolland M, JCEM, 2010) Observational study of 209 post-hip fracture subjects reported a 63% reduction in mortality (Beaupre LA, Osteoporosis Int, 2010) Observational study of nursing home subjects showed 27% reduction on mortality in BP users (Sambrook PN, Osteo Int, 2010) Prospective, cohort study of 2043 men and women over 60 demonstrated a 69% reduction in mortality in women on BPs (Center J, JCEM 2011) 8/21/2021 40
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Take Home Points ZA is effective in reducing fracture in older osteopenic women 4 infusions over 6 years was sufficient Decreased mortality and decreased cancer incidence in ZA treated women 8/21/2021 41
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Abaloparatide
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2–4 weeks 3–4 months Resting stage Reversal phase Formation Remodeling completed Activation Resorption Lining cells Osteoclast precursors Osteoclasts Osteoblasts Bone remodeling unit Lining cells Bone Remodeling
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PTH and PTHrp Bind to PTHR1 8/21/2021 44
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Abaloparatide Synthetic peptide analog of human PTHrp Potent anabolic agent for the treatment of osteoporosis in PMO Daily subcutaneous injection 2 years of therapy Must be followed by antiresorptive therapy 8/21/2021 45
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Abaloparatide Comparator Trial in Vertebral End point (ACTIVE) Randomized controlled and comparator 80 mcg abaloparatide, 20 mcg TPTD, injected placebo 18 months 2463 post menopausal women (1901 completed) 8/21/2021 PD Miller, JAMA, 2016 46
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ACTIVE: Abaloparatide v. Teriparatide 8/21/2021 Miller PD, JAMA, 2016 47
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ACTIVE: Fracture 8/21/2021 PD Miller, JAMA, 2016 48
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Side Effects Black Box: Contraindicated h/o skeletal irradiation, Pagets, mets, open epiphysis Hypercalcemia Urolithiasis Increased Uric acid Palpitations Hypotension 8/21/2021 49
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Take Home Points Abaloparatide is a potent anabolic agent used for those at high risk of fracture or for those who fail antiresoptive therapy More effective than teriparatide in reducing fracture especially at hip Patch delivery in development 8/21/2021 50
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Anti-Sclerostin Antibodies 8/21/2021 51
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2–4 weeks 3–4 months Resting stage Reversal phase Formation Remodeling completed Activation Resorption Lining cells Osteoclast precursors Osteoclasts Osteoblasts Bone remodeling unit Lining cells Bone Remodeling
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Wnt Signaling in Bone Canalis, 2013
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Romosozumab Administered by a health care professional 2 subcutaneous injections once a months for 12 months Must be followed by an antiresorptive 8/21/2021 54
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Romosozumab Bone Mineral Density 8/21/2021 55 McClung, NEJM, 2014 412 postmenopausal women with osteoporosis
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Cosman F et al. N Engl J Med 2016;375:1532-1543 Romozosumab-Denosumab Treatment in Women with PMO
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Cosman F et al. N Engl J Med 2016;375:1532-1543 Romosozumab-Denosumab Bone Density and Bone Markers Cosman, NEJM, 2016
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Cosman F et al. N Engl J Med 2016;375:1532-1543 Incidence of New Vertebral, Clinical and Nonvertebral Fractures Cosman F et al. N Engl J Med 2016;375:1532-1543
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Romosozumab-Alendronate 8/21/2021 Saag, NEJM, 2017 59
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Romosozumab-Alendronate 8/21/2021 60 Saag, NEJM, 2017
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Romozosumab OFF and Alendronate Pretreatment 419 postmenopausal women(55-85 y) Tscore -2.5-3.5 at LS , TH, or FN Rxed with 210 mg Q M for 2 years After 2 yrs, randomized to placebo or Dmab 60 mg q6 m McClung, JBMR 2018
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Romosozumab Off Effect and Effect of Alendronate Lead In Effect of Romo plateaus after 12 months Romo needs to be followed by antiresporptive therapy to prevent bone loss Bisphosphonates before Romo blunt response 8/21/2021 62 McClung, JBMR 2018
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Romozosumab v. Teriparatide 8/21/2021 63 Langdahl, Lancet 2017
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Side effects Black Box: CV (contraindicated in those with MI or stroke within a year) Arthralgia/myalgia Hypocalcemia Atypical femoral fracture Osteonecrosis of the jaw 8/21/2021 64
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Take Home Points Romosozumab is a potent bone anabolic agent used in severe osteoporosis or those that fail other therapy Vertebral fracture reduction>non vertebral Romo followed by Dmab is best CV side effects seen in clinical trials 8/21/2021 65
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Change in BMD at 24 months in Spine and Total Hip with Various Regimens 8/21/2021 66 McClung Osteo Sarc 2018
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Summary Fragility fracture is skeletal failure and must prompt evaluation and treatment Denosumab use for up to 10 years is safe and effective New data suggest that a limited course of Zoledronic acid even in those with osteopenia reduces fracture There are a variety of new treatment options for osteoporosis that can allow tailoring therapy to the individual characteristics “Medication Holiday” applies only to Bisphosphonates other agents including denosumab must be continued or followed by other therapy 8/21/2021 67
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Johns Hopkins Hospital Baltimore, Maryland 8/21/2021 68
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NNT vs. RR Atypical Fracture 8/21/2021 Black and Rosen, NEJM 2016 69
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Vertebral Fracture Risk in RCTs of Osteoporosis Treatments .53 .59 .48 .35 .50 .67 .66 .30 .62 .32
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Nonvertebral Fracture Risk in RCTs of Osteoporosis Treatments .80 .6 .5 .9 .88 .76 .75 .7 .80
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WHO, Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis, 1998. T-Score World Health Organization (WHO) Osteoporosis Definition SD
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Previous Guidelines Initiate pharmacologic treatment in: Those with a T score <-2.5 at the hip, spine or femoral neck Those with osteopenia and a FRAX 10 yr probability >20% of major osteoporotic fracture or >3% of hip fracture 8/21/2021 74
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What is FRAX®? The FRAX® tool has been developed by WHO to evaluate fracture risk of patients. It is based on individual patient models that integrate the risks associated with clinical risk factors as well as bone mineral density (BMD) at the femoral neck. The FRAX® models have been developed from studying population-based cohorts from Europe, North America, Asia and Australia. The FRAX® algorithms give the 10-year probability of fracture. The output is a 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture (clinical spine, forearm, hip or shoulder fracture).
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http://www.shef.ac.uk/FRAX/
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Screening for Osteoporosis DXA as indicated previously AND screening for asymptomatic vertebral fracture 8/21/2021 80
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Screen for Asymptomatic Fracture Vertebral Fracture in: Women over 70 and men over 80 with T score <-1.0 at hip, FN or spine Women over 65 and men over 70 with T score <-1.5 at hip, FN or spine Postmenopausal women and men age 50+ with specific risk factors Low trauma fracture during adult hood (age 50+) Historical height loss of 1.5 inches or more Prospective height loss of 0.8 inches or more Recent or ongoing glucocorticoid treatment 81
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Methods of Screening for Vertebral Fracture: Thoracic and Lumbar Xray DXA with VFA 8/21/2021 82
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Repeat Vertebral Imaging Repeat vertebral imaging only indicated if: Prospective height loss of 0.8 inches New back pain New postural changes 8/21/2021 83
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8/21/2021 84
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Take Home Points A fragility fracture is skeletal failure Measure and follow for height loss Screen for asymptomatic vertebral fracture Women over 70 and men over 80 with T score <-1.0 at hip, FN or spine Women over 65 and men over 70 with T score <-1.5 at hip, FN or spine Postmenopausal women and men age 50+ with specific risk factors 85
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Who should we screen with DXA measurements? ALL women age >65 and ALL men >70 Post menopausal women and men 50-70 with risk factors Adults 50+ with Low trauma fracture Radiographic evidence of osteopenia Long term glucocorticoid therapy Hypogonadal men Patients with hyperparathyroidism Patients with height loss >1.5 inches
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Combination and Sequential Therapies 8/21/2021 87
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DATA Study Design Lancet 382:50-56, 2013 100 Postmenopausal women 45+ years Open label, randomized, controlled trial for 1 yr “High fracture” risk: T-2.5 or less at spine, hip, FN T-2.0 or less with 1 BMD independent RF T score -1.0 or less with fragility fracture 1:1:1 randomization to TPT, Dmab, or both Outcome: BMD and bone markers 8/21/2021 88
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DATA: Change in BMD 8/21/2021 89
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DATA Switch DMAb to PTH or PTH to DMAb in PMO: Design: after 2 years of treatment switched to alternate treatment at 1 year PTH (27 women)and PTH/Dmab (21 women) combo treated switched to Dmab alone Dmab (24 women) treated switched to PTH Outcome BMD at 6 and 12 months ASBMR 2014, #1150
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Transition from Dmab to PTH or PTH to Dmab in PMO: DATA Switch
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DATA & DATA Switch Conclusion Combined TPT/Dmab increased BMD more than either agent alone TPT followed by Dmab resulted in greater increase in BMD Dmab followed by TPTresults in loss of BMD Combo treatment may be useful for treatment in very high risk patients 8/21/2021 92
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Romo Retreatment 8/21/2021 93 Kendler, Osteo Int, 2019
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Romo Retreatment: BMD and Bone Markers 8/21/2021 94 Kendler, OI, 2019