Rheumatology. keeping Joints in Motion. Treating and Preventing Fractures

Rheumatology keeping Joints in Motion Treating and Preventing Fractures Robin K. Dore, MD Clinical Professor of Medicine David Geffen School of Medicine at UCLA, Los Angeles CA Private practice, Tustin CA

Robin K. Dore, M.D. Clinical Professor of Medicine David Geffen School of Medicine at UCLA, Los Angeles, CA Department of Medicine Private practice, Tustin CA Clinical trials including anti-tnf for Amgen, Abbvie and Serono RANK ligand inhibitor (antibody) for Amgen IL1ra for Amgen and IL-1 TRAP for Regeneron PTH for Eli Lilly and Company and Allelix SERMs for Eli Lilly and Company Speaker, consultant and/or grant support from industry regarding osteoporosis Amgen, Eli Lilly and Company Intervention We have determined T-scores We know risk factors We have diagnosed and treated secondary causes of osteoporosis Our objective is to prevent fractures Who Do You Treat with Low Bone Mass (Osteopenia)? Postmenopausal women and men aged 50 years and older presenting with the following should be treated (after appropriate evaluation to exclude secondary causes): 6 Based on the US-adapted WHO algorithm of FRAX Low bone mass (T-score between -1.0 and -2.5 at the femoral neck, total hip, or spine); AND 10-yr probability of fracture greater than or equal to For the following type of fracture 3% Hip fracture 20% Any major osteoporosisrelated fracture Adapted from National Osteoporosis Foundation, 2008; www.nof.org.

Age 55 Sex F Wt 122 Ht 61 Fractur No e Parent Yes Fractur e GCs No R.A. Yes 2nd OP No Alcohol No FN -1.8 L1-4 -2.4 Quantifying Fracture Risk www.shef.ac.uk/frax 7 http://www.shef.ac.uk/frax/. Accessed 03/06/08 Treatment Goals Prevent fractures Stabilize or increase bone mass Relieve symptoms of fractures and skeletal deformity Affect patient s perceived goals of improving physical function Two Types of Drug Therapy for Osteoporosis Antiresorptive Lowers bone turnover Maintains or improves bone mass Anabolic Increases bone turnover with bone formation exceeding bone resorption, increases bone mass, and stimulates bone formation

Antiresorptive Therapy Mechanism of Increase in Bone Strength Number of Osteoclasts and Rate of Remodeling are Reduced Remodeling space filled Mineralization increases Initial + remodeling balance Prevents microstructural damage a) Trabecular plate perforation b) Loss of trabeculae c) Resorption stress risers BMD Increases Trabecular + to ++ Cortical 0 to + Architecture is preserved BMD contributes 3 to 30% of effect Decreased Fracture Incidence Preservation of architecture contributes 70 to 97% of effect Riggs BL, Parfitt AM. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res 2005;20:177-184. See also, Seeman E, Delmas PD. Bone Quality The Material and Structural Basis of Bone Strength and Fragility. N Eng J Med 2006:354:2250-2261 Anabolic Therapy (Teriparatide/abaloparatide) Mechanism of Increase in Bone Strength Increased Bone Remodeling (formation > resorption) Renewed periosteal modeling Positive remodeling balance Microstructural repair/ renewed trabecular modeling Improved bone geometry Increase BMD Trabecular +++ Cortical++ Improved architecture Decreased Fracture Incidence Riggs BL, Parfitt AM. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res 2005;20(2):177-184. Two Types of Drug Therapy for Osteoporosis Antiresorptive Anabolic Bisphosphonates Alendronate - Fosamax Teriparatide Forteo Risedronate - Actonel Abaloparatide-Tymlos Ibandronate - Boniva Zoledronate - Reclast Hormone therapy Estrogen Estrogen progestin therapy Selective estrogen receptor modulator Raloxifene - Evista RANKL inhibitor Denosumab (Prolia) Calcitonin Miacalcin, Fortical 1. Indicated for use in United States. Additional therapeutic options are approved in other countries.

Treating Low Bone Mass or Fracture Decision-Making in 2018 Patient Variables Age Fracture history FRAX score T-Score Concomitant medications Propensity to fall Compliance Side effect concerns (fears) Patient history, including GI Comorbid conditions Current Options Bisphosphonates SERMs Estrogen Calcitonin Parathyroid hormone/pthrp Denosumab The Basics Calcium Vitamin D Basic Intervention 2015 Updated Recommendation: Ensure adults age 50 and older have adequate calcium and Vitamin D intake, with supplementation only if necessary Calcium: 1000-1200 mg per day Vitamin D: 800 to 1000 IU per day (if 25-hydroxyl Vit D level nl) Other Avoid tobacco and excessive alcohol Physical therapy evaluation and instruction for cane or walker use Regular exercise to increase muscle tone and improve balance Occupational therapy to assess at-home fall risk Decrease fall risk review of medications, especially antihypertensive agents, sedativehypnotics and environment *National Osteoporosis Foundation s Updated Recommendations for Calcium and Vitamin D 3 Intake, 2016 Campion JM, Maricic MJ. Am Fam Phys. 2003;67(7):1521-1526. Indications for Treatment: NOF Guidelines Prior hip or vertebral fracture DXA hip or spine T-score <2.5 T-score between -1.0 and -2.5 with a 10- year risk of major osteoporotic fracture of >20% or a 10-year hip fracture of >3 NOF. Clinician s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2015

Behavioral/Lifestyle Measures to Prevent Osteoporosis Adequate intake of dietary calcium, vitamin D, and protein throughout life Regular physical activity; load-bearing exercise Minimize alcohol intake Stop smoking Take measures to prevent falls Use of hip protectors by patients prone to falling Ebeling PR. N Engl J Med. 2008;358:1474-1482; NOF. Clinician s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2010 Pharmacologic Treatment Options for Osteoporosis Antiresorptive agents Bisphosphonates Alendronate, risedronate, ibandronate, zoledronic acid SERMs Raloxifene Calcitonin RANKL inhibitor Denosumab Anabolic Teriparatide Abaloparatide RANKL = receptor activator of nuclear factor-κb ligand Bisphosphonates: Adverse Effects May include: All dosage forms a Nausea Heartburn Oral Irritation or burning of the esophagus Difficulty swallowing Painful swallowing Flu-like symptoms IV Arthralgia Myalgia Bone pain Fever Flu-like symptoms a Osteonecrosis of the jaw has been reported with oral bisphosphonates, but is extremely rare (affecting 1 in 10,000 patients). A greater degree of risk has been reported in cancer patients treated with high doses of IV bisphosphonates, exceeding levels used in osteoporosis. Khosla S, et al. J Bone Miner Res. 2007;1479-1491. National Osteoporosis Foundation. www.nof.org

Calcitonin Indications: Treatment of osteoporosis in women at least 5 years postmenopausal Significantly reduces risk of new vertebral fractures Available as nasal spray (recommended daily dose: 1 activation [200 IU]) or injection Not considered first-line monotherapy for osteoporosis Efficacy not demonstrated for nonvertebral or hip fractures Physicians' Desk Reference. 64th ed. Montvale, NJ; 2010. National Osteoporosis Foundation. www.nof.org Calcitonin: Adverse Effects Mild and of low incidence No serious adverse effects with long-term administration Most common adverse effects: Rhinitis: 12% Nasal symptoms: 11% Physicians' Desk Reference. 64th ed. Montvale, NJ; 2010. NOF. Clinician s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2010 National Osteoporosis Foundation. www.nof.org; Fortical Package Insert Raloxifene Indications: Prevention and treatment of osteoporosis in postmenopausal women Prevention of invasive breast cancer Significantly reduces risk of vertebral fracture Taken once daily (tablet) Not shown to reduce risk of nonvertebral or hip fractures Physicians' Desk Reference. 64th ed. Montvale, NJ; 2010. National Osteoporosis Foundation. www.nof.org

Raloxifene: Adverse Effects Incidence vs Placebo Adverse Effect Treatment Prevention Hot flashes 10% vs 6% 25% vs 18% Leg cramps 7% vs 4% 6% vs 2% Fluid retention 5% vs 4% 3% vs 2% Serious Adverse Event Hazard Ratio (95% CI) Deep vein thrombosis 2.4 (1.2-4.5) Physicians' Desk Reference. 64th ed. Montvale, NJ; 2010. National Osteoporosis Foundation.www.nof.org; Evista Package Insert Teriparatide Indications: Treatment of osteoporosis in postmenopausal women and men at high risk for fracture Treatment of women and men with glucocorticoid-induced osteoporosis at high risk for fracture Increasing bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture Significantly reduces risk of vertebral and nonvertebral fractures Self-administered daily injection from a preloaded pen Physicians' Desk Reference. 64th ed. Montvale, NJ; 2010. National Osteoporosis Foundation. www.nof.org/articles/22 Teriparatide: Adverse Effects a Adverse Event Incidence vs Placebo Leg cramps 3% vs 1% Dizziness 8% vs 5% Arthralgias 10% vs 8% Transient hypercalcemia 11% vs 2% a The FDA assigned a black box warning because of osteosarcoma findings in animal studies (no excess osteosarcomas were reported in human populations). Use limited to maximum of 2 years in a patient s lifetime. Physicians' Desk Reference. 64th ed. Montvale, NJ; 2010. National Osteoporosis Foundation. www.nof.org; Forteo Package Insert

Abaloparatide Indication: Treatment of postmenopausal women with osteoporosis at high risk for fracture defined as a history of osteoporotic fracture, multiple risk factors for fracture or patients who have failed or are intolerant to other available osteoporosis therapy Reduces the risk of vertebral and non-vertebral fractures Abaloparatide: Dosing and Administration 80mcg subcutaneously once daily Each pen contains 30 day supply of medication Does not need to be refrigerated once opened for use Cumulative use of abaloparatide and parathyroid hormone analogs (eg teriparatide) for more than two years during a patient s lifetime is not recommended Patients should receive supplemental calcium and Vitamin D if dietary intake is inadequate Abaloparatide Safety Abaloparatide caused a dose-dependent increase in the incidence of osteosarcoma in male and female rats when given 4 to 28 times the human dose It is unknown if abaloparatide increases this risk in humans Most common adverse reactions (incidence 2% or greater) include hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain and vertigo Avoid use in patients with pre-existing hypercalcemia and monitor urine calcium in patients with pre-existing hypercalciuria or active urolithiasis Orthostatic hypotension can occur so patients should be instructed to sit or lie down if symptoms develop

Indications: Denosumab Treatment of osteoporosis in postmenopausal women at high risk for fractures and to increase bone mass in men with osteoporosis at high risk of fracture Increase bone mass in men at high risk of fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer Increases BMD 1 Reduces risk of fracture versus placebo 2 20% nonvertebral 40% hip 68% new vertebral Available as twice yearly injection Human monoclonal antibody against RANKL 1. Bone HG, et al. J Clin Endocrinol Metab. 2008;93:2149-2157; 2. Cummings SR, et al. N Engl J Med. 2009;361:756-765; National Osteoporosis Foundation Available at: http://www.nof/org/articles/22 Denosumab: Adverse Effects Most common: Back pain, pain in extremities, musculoskeletal pain, high cholesterol levels, urinary bladder infections Serious adverse reactions: Infections of the skin, cellulitis Long-term safety being evaluated in 7-year extension to FREEDOM trial Data from the 2-year extension Continued increase of BMD during years 4 and 5 of treatment Fracture incident rates remained low and below those observed in the core trial placebo group Infectious events did not increase or decrease with long-term administration FREEDOM = Fracture Reduction Evaluation of Denosumab in Osteoporosis. Papapoulos S et al. J Bone Miner Res. 2012; 27: 694-701; Anastasilakis A. et al. Therapeutics and Clinical Risk Management. 2012; 8: 295-306; Prolia Package Insert Osteonecrosis of Jaw Rare, but potential complication of bisphosphonates, denosumab Most cases occur after dental extraction Most cases occur in cancer patients treated with high-dose IV bisphosphonate treatment Defined as area of exposed bone in the maxillofacial region that does not heal within 8 weeks Due to rare but serious adverse effects, a drug holiday after 5-10 years of bisphosphonate therapy should be considered National Osteoporosis Foundation. www.nof.org Anastasilakis A. et al. Therapeutics and Clinical Risk Management. 2012; 8: 295-306

Osteonecrosis of the Jaw (cont) Incidence in OP population:0.001%-0.01% Incidence in general population:<0.001% Other risk factors: glucocorticoids, jaw bone surgery, poor oral hygiene, chronic inflammation, ill-fitting dentures, diabetes, anti-angiogenic agents Preventive strategies: correct dental problems prior to initiating OP therapy, withhold OP therapy until surgical area heals Management: topical antibiotic oral rinses (Periodex) and oral antibiotics, perhaps TPTD Experimental therapies: BM stem cell intralesional transplant, platelet-derived GF, hyperbaric O2, low level laser therapy, tissue-grafting Atypical Femoral Fractures (AFF) Located anywhere along the femur from just distal to the lateral trochanter to just proximal to the supracondylar flare must be present in addition to 4/5 factors below) Associated with no or minimal trauma The fracture line originates at the lateral cortex and is substantially transverse in its orientation although it may become oblique as it progresses medially across femur Non-comminuted or minimally comminuted Complete fractures extend through both cortices or may be associated with a medial spike; incomplete fxs involve only the lateral cortex Localized periosteal/endosteal thickening of the cortex at the fracture site called beaking or flaring AFF (cont) Other findings may include: localized periosteal reaction of the lateral cortex, prodromal symptoms of dull or aching pain in the groin or the thighs, bilateral incomplete or complete femoral diaphysis fracture, delayed healing Pathophysiology: stress or insufficiency fractures that occur over time. The lateral cortex of the femur is known to sustain high levels of tensile stress due to bending which may precipitate damage in this location especially in those patients with lower limb geometry that could exacerbate that effect (eg, bowed femur, Asian race) No difference in mechanical or physical properties of bone in patients on long term BPs compared to controls

AFF (cont) Periosteal and endosteal surface calluses develop normally in patients with AFF and do not seem to be impaired by BP therapy In non-bp treated patients, complete fracture repair occurs by normal coupled bone remodeling but BPs localized at sites of high bone turnover, including those sites at which stress fractures are forming, suppress remodeling Schlichter et al: risk of AFF decreases by 70% after 1 year if BP stopped Dell et al: only 20% of contralateral femurs will fracture if BP stopped after first fracture compared to 50% if BP continued for 3 years AFF (cont) Evolve over time with initial development of cortical bump that likely represents periosteal thickening with eventual appearance of a transverse cortical lucency (fx) in the region of the periosteal thickening which may or may not progress to a complete fracture If cortical lucency seen on x-ray or DXA order an MRI Treatment: stop BP or Prolia, ensure adequate calcium and Vitamin D supplementation, prophylactice nail fixation for incomplete fractures with cortical lucency and pain but if no pain and incomplete fracture with periosteal thickening but no cortical lucency try nonweight bearing for 2-3 mos. If no response to conservative therapy, consider TPTD AFF Risk Factors Exposure to BPs greater than 3 years (median 7 years) Significant association with glucocorticoids Risk 3.2-50/100,000 patient years but with use over 5 years risk increases to >100/100,000

Long-term Management 37 Monitoring Patient To ensure that: Medication is taken regularly and correctly Calcium and vitamin D intake are sufficient The patient has no adverse effects or fear of adverse effects that must be addressed There are no comorbidities or other medications that might alter the expected treatment effect Assessing Treatment Failure If the BMD declines beyond least significant change: Rule out undiagnosed secondary problems Evaluate compliance and absorption issues National Osteoporosis Foundation. www.nof.org

Follow-Up for Postmenopausal Women and Men 50 Years of Age Individualize follow-up Those not requiring medical therapies should be re-evaluated for osteoporosis fracture risk Recent publication, suggests that osteoporosis would develop in less than 10% of older, postmenopausal women during rescreening intervals of 15 years for women with normal bone density Those taking FDA-approved osteoporosis medications should be re-evaluated at regular intervals Repeat BMD testing via DXA In general, every 1 to 2 years if on medication Otherwise, at 1- to 5-year intervals, depending on initial risk Duration of treatment remains a question; no long-term studies on efficacy and safety National Osteoporosis Foundation. www.nof.org; Gourlay ML et al NEJM 2012;366:225-233 Treatment Across the Lifespan Different agents might have different benefits/risks at different ages Osteoporosis treatment should be reviewed annually and length of treatment should be individualized Medical and fracture history Initial and recent bone mineral density test results The EMAS suggests changing OP therapy based on age, type of fracture risk (VFx vs non-vfx) and risk of fracture (moderate to high risk) Drug holidays may be considered in certain patients Keep patients involved in their care and aware of evolving concepts in osteoporosis National Osteoporosis Foundation. www.nof.org Extended Therapy with BPs BPs have a long residence in bone with release and possibly recycling of drug The half-life of BPs is estimated to be in years BUT differs for different bisphosphonates A recent study of BP discontinuation of ~14 mos 41% of subjects had detectable ALN in urine 0% of subjects had detectable risedronate in urine ALN has the longest half-life, risedronate the shortest and the half-life of ibandronate is unknown

Extended Therapy with BPs (cont) Given the long half-life in bone, it is probable that sufficient drug is retained so that the benefit of the BPs continues after therapy is stopped After completing 5 years of alendronate (FLEX) and 3 years of zoledronic acid (HORIZON-PFT Extension) The reduction in non-vertebral fractures is sustained for 3-5 years in most patients With continued therapy, there is ~50% lower risk of vertebral fractures FIT Long-Term Extension (FLEX) Women previously on alendronate for 3-6 years were randomly assigned to 5 years of alendronate (5 or 10 mg daily) or placebo Alendronate vs placebo Clinical spine fracture: RR=0.45 (0.23, 0.84) Morphometric spine fracture: RR=0.87 (0.61, 1.25) Nonspine fracture: RR=1.00 (0.76, 1.32) Black DM, et al. JAMA 2006;296:2927-2938 FLEX: % Change in Spine BMD Mean Percent Change From FIT Baseline, % 16 14 12 10 8 6 4 2 0 FIT 3 to 4.5 years Time Between FIT and FLEX 1 to 2 years FLEX 5 years F 0 F 1 F 2 F 3 F 4 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5 3.7% P<0.001 = ALN/Placebo (n = 437) = ALN/ALN (pooled 5-mg and 10-mg groups: n = 662) Year Black DM, et al. JAMA 2006;296:2927-2938

FLEX: % Change in Femoral Neck BMD Mean Percent Change From FIT Baseline, % 5 4 3 2 1 0 FIT 3 to 4.5 years Time Between FIT and FLEX 1 to 2 years FLEX 5 years 1.9% P<0.001 1 F 0 F 1 F 2 F 3 F 4 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5 = ALN/Placebo (n = 437) Year = ALN/ALN (pooled 5-mg and 10-mg groups: n = 662) Black DM, et al. JAMA 2006;296:2927-2938 FLEX: Incidence of Fractures Fracture Incidence, % Relative Risk Reduction = 55% ARR = 2.9% P = 0.013 RR = 0.45 CI (0.2, 0.8) ALN/PLB (n = 437) ALN/ALN (n = 662) RR = 0.9 CI (0.6, 1.2) RR = 1.0 CI (0.8, 1.4) 5.3% 2.4% 11.3% 9.8% 19.0% 18.9% Clinical Vertebral Vertebral Morphometric Non-Vertebral Black DM, et al. JAMA 2006;296:2927-2938 HORIZON-PFT Extension: Secondary Endpoint New Morphometric Vertebral Fractures Continuous treatment with ZOL for 6 years resulted in significantly fewer new morphometric vertebral fractures in years 3-6 than discontinuation of treatment (ITT) 15 PBO ZOL Core Study (Yr 0-3) Z3P3 Z6 10.9% (310/2853) 70% (62, 76) % Patients 10 5 3.3% (92/2822) 6.2% (30/486) 52%* (10, 74) 3.0% (14/469) 0 Core study 1 Extension study Morphometric Vertebral Fractures Core study: P < 0.001 relative risk reduction vs placebo (PBO) *P = 0.0348, relative risk reduction vs Z3P3; n = the number of patients in the analysis population with X-rays at Year 3 and Year 6 1 Black DM, et al. N Engl J Med. 2007;356:1809 1822. 2 Black DM, et al. Abstract 1070 and oral presentation October 16, 2010. ASBMR 2010 Annual Meeting, Toronto, Canada. 48

HORIZON-PFT 2301E1: Secondary Endpoints Nonvertebral Fractures % Patients 15 10 5 Discontinuation of ZOL resulted in a similar risk of nonvertebral fracture to continuous treatment in years 3-6 (ITT) 10.7% 25%* (13, 36) 8% Relative hazard (RH)=0.99 (0.66, 1.50) 7.6% 8.2% 0 Core study 1 Extension study Nonvertebral Fractures PBO ZOL Core Study (Yr 0-3) Z3P3 Z6 *P < 0.001; The event rate is from Kaplan-Meier estimate at Month 36 in the extension study 1 Black DM, et al. N Engl J Med. 2007;356:1809 1822. 2 Black DM, et al. Abstract 1070 and oral presentation October 16, 2010. ASBMR 2010 Annual Meeting, Toronto, Canada. 49 Managing Osteoporosis in Patients with Long-Term Bisphosphonate Use: Report of a Task Force of the American Society of Bone and Mineral Research January 2016 The ASBMR focused on the risk (ONJ and AFF) and benefit (vertebral fracture reduction) Based on the FLEX and HORIZON trials, women at high risk of fracture should continue bisphosphonates for 10 years (oral) and 6 years (IV) High risk of fracture is defined as older women, low hip T-score, high FRAX score, prior major osteoporotic fracture or fracture on therapy Women at low risk of fracture should be treated with 5 years of oral bisphosphonate or 3 years of IV therapy with a drug holiday considered with a length of 2-3 years It is unknown if these recommendations should be applied to men as too few men were included in the HORIZON trials and none in the FLEX trial It is not recommended to take a drug holiday for patients on steroids ASMBR Task Force Recommendations 2016 (continued) If the patient still has osteoporosis after being treated for these periods of time with bisphosphonates, a bisphosphonate drug holiday but not a drug holiday should be taken After using bisphosphonates for these periods of time, consider using non-bisphosphonate therapy such as denosumab, teriparatide or raloxifene Use of teriparatide is limited to 24 months. After this period of time, another bone-active therapy should be initiated to prevent bone loss after completing teriparatide therapy Patients treated with denosumab should not be given a drug holiday, as there is no skeletal retention and bone loss occurs immediately after discontinuation of denosumab Raloxifene is only indicated for treatment of women