MonashHealth Refracture Prevention The Role of Primary Care Professor Peter R Ebeling AO MBBS MD FRACP Head, Department of Medicine School for Clinical Sciences Monash Health Translation Precinct Monash University, Clayton, Victoria Potential Conflicts Departmental research funding from Merck, Novartis, Amgen and Eli-Lilly Honoraria to Department from Amgen, Gilead and Eli-Lilly The Annual Women s and Children s Health Update 1 th June 1 The Crisis in the Treatment of Osteoporosis Declining Osteoporosis Treatment Rates Post-hip Fracture MonashHealth MonashHealth Media Tries to Provide a Positive Message Half of Hip Fracture Patients Give Us Advance Notice Opportunities for GP intervention Hip fracture is all too often the final destination of a thirty year journey fuelled by decreasing bone strength and increasing falls risk MonashHealth 1. J Endocrinol Invest 1999;3:53-5 Kanis JA & Johnell O. Osteoporosis Review. 9;17(1):1-1 Mitchell PJ 1
Diagnosis WHO Criteria for Osteoporosis Confusing! T-score Normal > 1 Osteopenia* 1 to.5 Osteoporosis.5 Severe osteoporosis.5 and 1 fracture Absolute Fracture Risk www.fractureriskcalculator.com For every 1 SD from normal, the relative risk of fracture increased by 1.5- to.5- fold *Most fractures (~7%) occur in women with osteopenia Reference standard for normal BMD is a 3-year-old healthy woman Kanis JA, et al. J Bone Miner Res. 199;9:1137-111. National Osteoporosis Foundation, 3. Vitamin D + Ca in Institutionalised Elderly 37 women, mean age, living in nursing homes, randomised to 1.g Ca + IU Vit D or placebo for 1 mths Vitamin D Plus Calcium Supplementation and Fractures in Community Dwelling Adults > 5 Years of Age % 1 1 p<.15 All Nonvertebral p<. Hip Vit D + Ca Chapuy et al, NEJM, 199 Zhao J-G et al, JAMA 17; 31():-
Secondary Prevention: RECORD Trial Recent low trauma fracture Effect of calcium supplements with or without vitamin D on cardiovascular events: Based on patient-level data n 59 Setting Comm Dose IU 5OHD 3 Adherence 5% Grant AM et al. Lancet 5 Bolland M J et al. BMJ 11;3:bmj.d 11 by British Medical Journal Publishing Group MI Risk and Baseline Risk Factors Cardiovascular Events in RCT of 5 Yrs Calcium vs &.5 Yrs Follow up in 1 Postmenopausal Women ITT Analysis Bolland M J et al. BMJ 1 31:C391 Lewis J et al. J Bone Miner Res (epub July 1) Health Benefits of Higher Dietary Calcium Intakes Khan B et al., J Bone Miner Res 15;3:175- Effects of Calcium on Myocardial Infarction Numerous large studies of Ca plus vitamin D have shown no increased risk of cardiovascular events However, concern exists that MI risk is increased Food remains the best source of calcium Supplements should be used only when adequate dietary Ca intake cannot be achieved Beneficial effects of calcium are found with relatively low doses (5- mg) In almost every osteoporosis treatment RCT, adequate Ca and vitamin D were also required Elderly individuals and others with impaired renal function who take calcium supplements may be at higher risk of CVD 3
Percent Change (LS Mean ± SE) Percent Change (LS Mean ± SE) Incidence at Month 3 (%) Vitamin D Reduces Falls Meta-analysis showed that vitamin D supplementation reduces falls by % in ambulatory or institutionalised elderly individuals 15 patients would need to be treated with vitamin D to prevent one fall Should be part of multi-faceted falls prevention program Larger doses of, IU per mth, or 5, IU per yr, are associated with an increased falls risk Bischoff-Ferrari HA et al., JAMA, 1 Position Statement Risks and Benefits of Sun Exposure 1 - CCV, ACD, OA, ANZBMS, ESA UV Index >3: A few minutes of mid-morning or mid-afternoon sun exposure to arms and hands (or equivalent area) on most days of the week should be sufficient to maintain adequate vitamin D levels UV Index <3 (May-August in southern states): Sun protection is not recommended - During these times, to support vitamin D production it is recommended that people be outdoors in the middle of the day with some skin uncovered on most days of the week - Being physically active while outdoors will further assist with maintaining vitamin D levels. A brisk walk at lunchtime or gardening are examples of being physically active outdoors Tailoring Therapy- Which Option for Who? First-line drugs for osteoporosis are anti-resorptive The Effect of Denosumab on Fracture Risks at 3 Months FREEDOM Trial Oestrogen +/- progestogen, if menopausal symptoms are present Selective oestrogen receptor modulating drugs (e.g. raloxifene) 9% % RR = % P <.1.% RR = % P =.1 Denosumab Oral bisphosphonates (alendronate, risedronate) 7% 7.% Intravenous bisphosphonates (zoledronic acid) Subcutaneous denosumab injections (human RANK ligand Ab) % 5% % NNT =.5% NNT = NNT = Second-line drugs Stimulates bone formation [subcutaneous PTH(1-3) or teriparatide injections] Strontium ranelate (uncertain mode of action; CV safety) 3% % 1% %.3% 1.% RR = % P =. New Vertebral Nonvertebral Hip.7% RR = risk reduction Cummings SR, et al. N Engl J Med. 9;31:75-75. Denosumab Re-treatment and Changes in Lumbar Spine and Total Hip BMD Phase Study in Women With Low BMD Lumbar Spine 1 1 1 - - 1 1 3 Months Discontinued Treatment Re-treatment mg QM - - Total Hip - 1 1 3 Months 3 mg Q3M Discontinued Treatment Re-treatment mg QM FREEDOM Extension Study Design R A N D O M I Z A T I O N FREEDOM EXTENSION Year a 1 3 5 7 9 1 Year a Denosumab mg SC QM (N = 3,9) SC QM (N = 3,9) Denosumab mg SC QM (N =,33) Calcium and Vitamin D Denosumab mg SC QM (N =,7) 1 3 5 7 Long-term denosumab treatment Crossover denosumab treatment Miller PD, et al. Bone. ;3:-9 a Year = years of denosumab treatment. Bone HG et al. Lancet Diabetes Endocrinol 17;5:513 53.
Total Hip Percent Change From Baseline Effect of 7 or 1 Years Treatment with Denosumab on Vertebral and Non-vertebral Fractures FREEDOM Extension Trial Effect of 7 or 1 Years Treatment with Denosumab on Spinal and Total Hip BMD FREEDOM Extension Trail Bone HG et al., Lancet Diabetes Endocrinol. 17; 5:513-53. Bone HG et al., Lancet Diabetes Endocrinol. 17; 5:513-53. 5 Why Change Therapy? Sequential therapy for osteoporosis may be considered When there has been significant bone loss or a fracture on antiresorptive therapy for >1 months In the presence of adverse events Insufficient adherence, e.g. the elderly Dosing inconvenience or intolerance with oral bisphosphonate therapy Patients with CKD where bisphosphonates are contraindicated To consolidate increases in BMD following anabolic therapy MonashHealth Head-to-head Studies of Denosumab vs Bisphosphonates in Both Pre-treated or Treatment-naïve Subjects Pre-treated 1.%* RIS Pre-treated 1.%* IBN Pre-treated.9%* 1.%* Treatmentnaïve Data are least-squares means and 95% confidence intervals. *p <.1 denosumab vs BP. 1 Recknor C et al. ASBMR Poster FR3. Kendler DL et al. J Bone Miner Res. 1;5:7-1. 3 Brown JP et al. J Bone Miner Res. 9;:153-11 Menu Roux C et al, ASBMR; Minneapolis, MN; October 1-15, 1. This information has been provided to you in response to your unsolicited request. ALN ALN 1 3 PBS Reimbursement for Teriparatide in Patients with Severe Osteoporosis Severe osteoporosis Radiographic Features T score < -3. minimal trauma fractures One fracture occurred after 1 mths of antiresorptive drugs Or, intolerance to oral and intravenous bisphosphonates and denosumab Treatment initiated by specialist, but may be continued by GP - limited to 1 months per lifetime Short-oblique configuration No comminution Medial spike Diffuse cortical thickening Focal lateral cortical thickening ( beaking ) 5
Early Detection - Radionuclide Bone Scintigraphy - Risk of Atypical Femoral Fracture Associated with Bisphosphonate Use during the 3 Years (5 ) Preceding the Fracture. Schilcher J et al. N Engl J Med 11;3:17-1737 Clinical Features I Prodromal pain in 7% (15 of 7) Concomitant GC use in 3% ( of 7) incr fracture risk in one large series (OR 5.) Bilateral fractures present in % ( of 15) Bilateral radiological changes present in % (3 of ) Delayed healing in % (9 of 11) Physician and Patient Education The majority have a prodrome of thigh or groin pain Educate physicians and patients about this symptom physicians to ask patients on BPs and other potent antiresorptive agents about thigh or groin pain Urgent radiographic evaluation of both femora (even if pain is unilateral) is needed if plain radiographs are normal, MRI or radionuclide scintigraphy scans should be performed Jaw Osteonecrosis Medication Related- Osteonecrosis of the Jaw (MRONJ) Area of exposed bone in maxillofacial region that has been present for more than weeks 1 Khosla S et al (7); JBMR Associated with bisphosphonates and denosumab Incidence IV bisphosphonates and malignancy (. 1%) Oral bisphosphonates and osteoporosis (1/1,-1/1,) Impaired QOL and chronic sequelae Often does not resolve in oncology cases Miksad et al (11); Oncologist
Cumulative incidence, % Patients with new vertebral fractures (%) BMD change from FIT baseline mean % Frequency of MRONJ Benign Indications Retrospective assessment ASBMR consensus rep. 1/1,-1/1, German study 1/13,5 ADA < 1/1, Canadian study < 1/1, Kaiser-Permanente 1/95-1/1,537 Prospective assessment HORIZON (>1, pts) BP/1 placebo (incl follow up study),, pts used zoledronic acid so far Not a single ONJ case reported Risk in oncology trials is much higher 1-% In oncology trials, denosumab has the same risk of ONJ as zoledronic acid also 13 pts in osteoporosis 7-year FREEDOM trial extension with denosumab Risk Factors for ARONJ Age > 5 yrs Periodontitis Use of bisphosphonates > yrs Smoking Denture wearing Diabetes mellitus Invasive bone procedures such as tooth extractions Antiresorptive Drug Holidays Insufficient evidence to recommend a holiday from Antiresorptive drug therapy or waiting periods before performing dental treatment for prevention of ARONJ Hellstein JW et al, JADA 11 Significant therapeutic benefits of AR agents in patients with osteoporosis far outweigh the small risk of developing ARONJ There is no drug holiday for denosumab McClung M et al, JBMR 1 How Long to Continue Bisphosphonate Therapy? Effect of Continuing or Stopping Alendronate after 5 Years of Treatment on Total Hip BMD 1 1 1 1 - FIT Black et al JAMA ;9:97-93 Total Hip FLEX 1 3 1 3 5 Year Year Alendronate 5 5 * 57 599 5 553 37 3 3 3 97* 37 15 1 3 31 *Measured in clinical fracture arm only. All subjects had received alendronate during FIT. FLEX treatment group Alendronate (pooled) Effect of Continuing or Stopping Alendronate After 5 Years of Treatment on Clinical Vertebral Fractures Effect of Continuing or Stopping Zoledronate After 3 Years of Treatment: Fractures 15 1 Clinical vertebral fractures RR,.5 (.-.) FLEX treatment group Alendronate (pooled) 15 1 Core PBO 1.9% Morphometric vertebral fractures Z3P3.% Odds ratio =.51 (.-.95) Increase in vertebral fractures if stop ZOL after 3 years 5 1 3 7 5 Core ZOL 3.3% Z 3% Time to first fracture, mo No. at risk 37 9 1 17 1 Alendronate 59 57 5 5 Extension study (year 3-) Black et al JAMA ;9:97-93 Black et al J Bone Miner Res 1;7:3-5 7
Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of ASBMR Thank You! Adler RA et al., J Bone Miner Res 1