2016 AACE/ACE POSTMENOPAUSAL OSTEOPOROSIS GUIDELINES: Practical Applications. Outline. The Process. Osteoporosis Diagnosis NEW CLINICAL DEFINITION

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1 2016 AACE/ACE POSTMENOPAUSAL OSTEOPOROSIS GUIDELINES: Practical Applications Steven M. Petak MD, JD, MACE, FACP Associate Clinical Professor Weill-Cornell Medical College Division Head and Chief of Endocrinology Houston Methodist Hospital Houston, Texas Outline Diagnosis Workup and evaluation Treatment choices Rare adverse events Drug holidays Sequential and combination therapy Treatment Algorithm AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS 2016 Co-Chairs: Pauline M. Camacho, MD, FACE; Steven M. Petak, MD, MACE, FACP, JD Committee: Neil Binkley, MD; Bart L. Clarke, MD, FACP, FACE; Steven T. Harris, MD, FACP Daniel L. Hurley, MD, FACE; Michael Kleerekoper, MBBS, MACE; E. Michael Lewiecki, MD, FACP, FACE; Paul D. Miller, MD; Harmeet S. Narula, MD, FACP, FACE; Rachel Pessah-Pollack, MD, FACE; Vin Tangpricha, MD, PhD, FACE; Sunil J. Wimalawansa, MD, PhD, MBA, FCCP, FACP, FRCP, DSc, FACE; Nelson B. Watts, MD, FACP, MACE 2 years of work 14 authors 313 references 42 recommendations The Process At least 20 versions of the manuscript 7 versions of the algorithm! Osteoporosis Diagnosis NEW CLINICAL DEFINITION Osteoporosis should be diagnosed based on: Presence of fragility fractures in the absence of other metabolic bone disorders T-score of 2.5 or lower in the lumbar spine (AP), femoral neck, total hip, and/or 33% (1/3) radius even in the absence of a prevalent fracture

2 Osteoporosis may also be diagnosed in patients with osteopenia and increased fracture risk using FRAX country-specific thresholds NBHA Position Statement: Clinical Diagnosis of Osteoporosis In postmenopausal women and men age 50 years and older, osteoporosis may be diagnosed by. T-score -2.5 at the LS, TH, or FN Low trauma hip fracture regardless of BMD Osteopenia with low trauma vertebral, proximal humerus, pelvis or some distal forearm fractures FRAX MOF risk 20% or HF risk 3% Siris ES et al. Osteoporos Int. 2014;25: NBHA Position Statement: Clinical Diagnosis of Osteoporosis In postmenopausal women and men age 50 years and older, osteoporosis may be diagnosed by: T-score -2.5 at the LS, TH, or FN Low trauma hip fracture regardless of BMD Osteopenia with low trauma vertebral, proximal humerus, pelvis or some distal forearm fractures FRAX MOF risk 20% or HF risk 3% Implications of the New Clinical Definition More patients will be labeled with the diagnosis Increased capture of high risk patients Increased coverage for DXA/labs and medications More accurate government cost appropriation for osteoporosis Siris ES et al. Osteoporos Int. 2014;25: Case 1 75 year old Caucasian female 140 lbs, 64 inches tall + Maternal history of hip fracture No history of prior fractures No smoking, significant alcohol intake No RA, glucocorticoid use Lumbar spine T score -2.1, Femoral neck T score -2.3 FRAX score: 14% major osteoporotic fracture and 4.5% hip fracture Thus she has osteoporosis based on new clinical definition DXA/labs can be covered as well as appropriate medications

3 Workup and Evaluation Evaluation for Secondary Osteoporosis Complete blood cell count Serum chemistry, including calcium, phosphate, total protein, albumin, Liver enzymes, alkaline phosphatase, Serum creatinine, and electrolytes 24-h collection for calcium, sodium, and creatinine excretion Serum 25-hydroxyvitamin D Causes of Secondary Osteoporosis Intact PTH TSH Tissue transglutaminase SPEP and free light chains Serum tryptase Urinary free cortisol Bone biopsy Endocrine or metabolic Nutritional/GI Drugs Disorders of Othe r causes conditions collagen metabolism Ac rome galy Alc oholis m Antiepileptic drugs b Ehlers -Da n l o s AIDS/HIV a Diabetes mellitus Anorexia nervosa Aromatase inhibitors syndrome Ankylosing spondylitis Type 1 Ca l c i u m de fici en c y Ch e mo the ra p y / Ho mo c y s tin u ria due Ch ro n i c ob stru ctive Type 2 Chronic liver disease immunosuppressants to cystathionine pulmonary disease Growth horm one Ma l a b s o rp t i on De p o -Prov era deficiency Gaucher disease deficiency syndromes/ Gl u c o c o rti co i ds Marfan syndrome He mo p h i l i a Hy perc ortisolism ma l n u t ri t i o n Go n a d o trop i n-releasing Os te o g e n e si s Hy p e rc a l c iu ri a Hy perpara thyroidism (inc luding c eliac hormone agents imperfect Immobilization Hy perthyroidism disease, cystic He p a ri n Major depression Hy pogonadism fibrosis, Crohn s Lithium My e l o ma a n d so me Hy pophosphata sia disease, and gastric Proton pump inhibitors cancers Porphyria res ec tion or bypass) Selec tiv e s erotonin reuptake Organ transplantation Pregnancy Total parenteral inhibitors Re n a l in s u fici en c y/ nutrition Thiazolidinediones failure Vitamin D deficienc y Thyroid hormone (in Renal tubular acidosis supraphysiologic doses) Rheumatoid arthritis Systemic mastocytosis Thalassemia Causes of Secondary Osteoporosis Recommend all patients with osteoporosis undergo evaluation Present in up to 40% of patients who are tested Tannenbaum C, Clark J, Schwartzman K, Wallenstein S, Lapinski R, Meier D, Luckey M 2002 Yield of laboratory testing to identify secondary contributors to osteoporosis in otherwise healthy women. J Clin Endocrinol Metab 87: [EL 3; CSS] Case 2 65 year old with no prior fractures Lumbar spine T score -2.5, Femoral neck T score -1.8 Secondary workup revealed: 25 OHD- 13 ng/ml Intact PTH- 120 pg/ml ( normal pg/ml) Serum calcium- 8.6 mg/dl, Phos- 2.9 mg/dl, 24 urine calcium- 95 mg/24 hours Positive celiac antibodies

4 Case 2 65 year old with no prior fractures Lumbar spine T score -2.5, Femoral neck T score -1.8 Secondary workup revealed: 25 OHD- 13 ng/ml Intact PTH- 120 pg/ml ( normal pg/ml) Serum calcium- 8.6 mg/dl, Phos- 2.9 mg/dl, 24 urine calcium- 95 mg/24 hours Positive celiac antibodies Would recommend correcting her vitamin D deficiency, secondary hyperparathyroidism and hypocalciuria Recommend GI biopsy/gluten free diet Ensure that the patient does not have osteomalacia by biochemical tests ( high alkaline phosphatase) Antiresorptive therapy can later be started after repletion Current Medications for Osteoporosis INITIAL CHOICE OF AGENT Inhibit Bone Resorption Alendronate (Fosamax, generic) Risedronate (Actonel, Atelvia, generic) Ibandronate (Boniva, generic) Zoledronate (Reclast, generic) Denosumab (Prolia) Raloxifene (Evista, generic) Calcitonin (Miacalcin, Fortical) Estrogen (various) Strontium ( dual effect) Stimulate Bone Formation Teriparatide (Forteo) FDA Approved Agents and Effect on Fracture Risk Drug Calcito n in (Miacalcin, Fortical ) Raloxifene (Evista ) Ibandronate(Boniva ) Vertebral Fracture ü ü ü Nonvertebral Fracture Hip Fracture Alendronate (Fosamax ) ü «ü Rised ro n ate (Actonel, Atelvia ) ü ü «Zoledronic acid (Reclast ) ü ü ü Denosumab (Prolia ) ü ü ü Teriparatide (Forteo ) ü ü Recommendations on initial choice of agent Approved agents with efficacy to reduce hip, nonvertebral, and spine fractures including alendronate, risedronate, zoledronic acid and denosumab, are appropriate as initial therapy for most patients at high risk of fracture Teriparatide, denosumab or zoledronic acid should be considered for patients unable to use oral therapy and as initial therapy for patients at especially higher fracture risk Raloxifene or ibandronate may be appropriate initial therapy, in some cases, for patients requiring drugs with spine-specific efficacy

5 Risk Stratification Moderate fracture risk : Alendronate, risedronate, denosumab, or zoledronic acid Higher fracture risk: Denosumab, teriparatide or zoledronicacid Higher fracture risk category: Older age Prior fractures Very low T score High fall risk Glucocorticoids Case 3 68 year old female with no prior fractures Lumbar spine T score -2.6, Femoral neck T score -2.4 Maternal history of osteoporosis No other risk factors for fracture Secondary workup just showed vitamin D deficiency which has been corrected No GI issues Treatment choices: oral bisphosphonates (alendronate or risedronate) If the patient is unable to tolerate oral BP s, or as first line therapy: denosumab or zoledronic acid Case 4 85 year with multiple vertebral compression fractures, last one was 2 months prior Lumbar spine T score -3.3, Femoral neck T score -3.5 Maternal history of hip fracture History or primary hyperparathyroidism s/p subtotal parathyroidectomy 6 years prior Secondary evaluation- vitamin D/calcium replete. The rest of the workup was fine. Patient has a very high fracture risk and is likely to suffer from another compression fracture Treatment options: Teriparatide, denosumab, zoledronic acid

6 RARE ADVERSE EVENTS Rare but Serious Adverse Events (SAEs), namely Atypical Femoral Fractures (AFF) and Osteonecrosis of the Jaw (ONJ), have raised concerns regarding the prolonged use of such drugs The long term retention of BPs in bone, and the serious AEs, led to the concept of drug holiday, to maximize benefits and minimize harms Osteonecrosis of Jaw Bisphosphonate-Associated Osteonecrosis of the Jaw Report of a Task Force of the ASBMR * Osteonecrosis of the jaw (ONJ) definition The presence of exposed bone in the maxillofacial region that did not heal within 8 weeks after identification by a healthcare professional ONJ rarely associated with oral bisphosphonates Estimated between 1 in 10,000 and 1 in 100,000 patient-years The ASBMR report recommends: Patients should be informed that the risk of developing bisphosphonateassociated ONJ with routine oral therapy for osteoporosis or Paget's disease seems to be low, ranging between 1/10,000 and 1/100,000 [per year] * ASBMR = American Society for Bone and Mineral Research Khosla S, et al. J Bone Miner Res. 2007;22: SUBTROCHANTERIC FRACTURES OF THE FEMUR How common are these fractures? Preliminary estimates of atypical femoral fracture incidence based on an HMO database ( 2.6 M people > 45) Progressive increase from 2 per 100,000 cases per year for 2 years of BP use to 78 per 100,000 cases per year for 8 years of BP use. Watts NB and Diab D, J Clin Endocrinol Metab 2010;95: Dell R, Greene D, Ott S, et al. A retrospective analysis of all atypical femur fractures seen in a large California HMO from the years 2007 to 2009.

7 Bonus Features! Section on patient communication of rare adverse events Printable materials ( illustrating benefit/risk of treatment DURATION OF THERAPY Evidence used for recommendations FLEX trial HORIZON study extension Clinical experience Clinical Vertebral Fractures in the FLEX Study Cumulative Incidence of Fractures (%) ALN 5 years Placebo 5 years Alendronate 10 years RR 55% P = Years Since FIT ALN/PLB ALN/ALN % 2.5% Blac k DM, et al. JAMA. 2006;296: Recommendations on Optimum Duration of Therapy For oral bisphosphonates, consider a bisphosphonate holiday after 5 years of stability in lower-risk ( or moderate risk) patients For oral bisphosphonates, consider a bisphosphonate holiday after 6 to 10 years of stability in higher-risk patients Treatment with teriparatide should be limited to 2 years For IV zoledronic acid, consider a drug holiday after 3 annual doses in lower-risk (moderate risk) patients and after 6 annual doses in higher-risk patients. Teriparatide or raloxifene may be used during the bisphosphonate holiday period for higher-risk patients

8 Back to Case 3 A drug holiday is not recommended with denosumab 68 year old female with no prior fractures Lumbar spine T score -2.6, Femoral neck T score -2.4 Maternal history of osteoporosis No other risk factors for fracture Secondary workup just showed vitamin D deficiency which has been corrected No GI issues Back to Case 4 Treatment choices: oral bisphosphonates (alendronate or risedronate) If the patient is unable to tolerate oral BP s, denosumab or zoledronic acid If on oral bisphosphonatesà drug holiday after 5 years If on zoledronic acid à drug holiday after 3 years If on denosumab à continuous therapy 85 year with multiple vertebral compression fractures, last one was 2 months prior Lumbar spine T score -3.3, Femoral neck T score -3.5 Maternal history of hip fracture History or primary hyperparathyroidism s/p subtotal parathyroidectomy 3 years prior Secondary evaluation- normal on calcium and ergocalciferol Patient has a very high fracture risk and is likely to suffer from another compression fracture Choice 1: Teriparatide Other options: Denosumab, zoledronic acid If on teriparatideà stop at 2 years and switch to antiresorptive therapy If on denosumabà continuous therapy If on zoledronic acidà drug holiday after 6 years ON COMBINATION THERAPY

9 Case 5 AACE does not recommend concomitant use of antiresorptive agents for prevention or treatment of postmenopausal osteoporosis (no fracture data) If estrogen is being given for treatment of menopausal symptoms or raloxifene is being given to reduce the risk of breast cancer, an additional agent such as a bisphosphonate, denosumab, or teriparatide may be considered 47 year old female who had early menopause ( age 35) Was on HRT since menopause Lumbar spine T score -3.6, Femoral neck T score -4.0 Family history of osteoporosis and kidney stones No prior fractures or other causes of bone loss Secondary workup : 24 urine calcium 450 mg/24 hours. Add antiresorptive therapy to her HRT Start thiazide diuretic for idiopathic hypercalciuria Combined denosumab and teriparatide achieves improved BMD response versus either agent alone but no fracture data are available. However this combination could be considered for patients failing denosumab Effect of Combined Denosumab and Teriparatide ON SEQUENTIAL THERAPY Leder et al, JCEM 2014

10 Treatment with teriparatide should always be followed by antiresorptive agents to prevent bone density decline and loss of fracture efficacy Several studies on teriparatide discontinuation showed BMD loss ( PMO, premenopausal women, men) if not followed by antiresorptive therapy Leder 2009, Cohen 2015, Fracture When is the drug holiday over? AACE/ACE 2016 POSTMENOPAUSAL OSTEOPOROSIS ALGORITHM BMD decline Rise in bone turnover markers may be a signal that the holiday should be over, but does not apply to those with low BTM s prior to treatment

11 AACE/ACE Recommendations Risk stratification ( no prior fractures and moderate fracture risk vs prior fractures and higher fracture risk) determines initial choice of therapy and duration of therapy. Moderate fracture risk: 5 years of oral BP, 3 years of ZA Higher fracture risk: 10 years of oral BP, 6 years of ZA For patients who are losing bone on therapy or with recurrent fractures- moderate fracture risk group Assess compliance Re-evaluate for causes of secondary osteoporosis If on oral BP, switch to injectable antiresorptive If on injectable antiresorptive, switch to teriparatide Duration of Treatment for Higher Fracture Risk Group Denosumab- continue therapy Teriparatide- continue therapy for up to 2 years, then sequential therapy ZA- continue therapy for up to 6 years, then drug holiday Consider using another agent during drug holiday For patients who are losing bone on therapy or with recurrent fractures- higher fracture risk group If on denosumab- consider adding teriparatide If on zoledronic acid- consider switching to teriparatide

12 How are patients monitored during drug holidays? Annual visits to assess clinical state and fractures DXA every 1-2 years Bone turnover markers Ensure vitamin D and calcium sufficiency Fall prevention advice When is the holiday over? When a fracture occurs BMD loss beyond LSC BTM increase to pretreatment levels Clinically the patient s fracture risk increases significantly ( eg, treatment with high dose steroids, or significant increase in fall risk) What happens after the drug holiday? Start another cycle of bisphosphonate therapy Patients who are at highest risk for fractures can be switched to anabolic therapy Patients previously treated with bisphosphonates can switch to denosumab Conclusions Significant advances are happening in the diagnosis, prevention and treatment of osteoporosis The 2016 AACE/ACE Postmenopausal Guidelines have updated recommendations on the diagnosis, treatment and long term follow up of patients with osteoporosis Be sure to download your copy from aace.com THANK YOU FOR YOUR ATTENTION