Everything a Pharmacist Needs to Know About Osteoporosis New Mexico Pharmacists Association Mid-Winter Meeting January 27-28, 2018 Albuquerque, NM E. Michael Lewiecki, MD, FACP, FACE Director, New Mexico Clinical Research & Osteoporosis Center Director, Bone Health TeleECHO University of New Mexico Health Sciences Center Albuquerque, NM

Disclosure Consulting Amgen, Radius Speaking Radius

Objectives Recognize osteoporosis treatment guidelines Define balance of benefits and risk with treatment Demonstrate risk communication techniques

Osteoporosis A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture Bone strength reflects the integration of two main features: bone density and bone quality NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. March 27-29, 2000. Published in JAMA. 2001;285:785-795. Images by David Dempster, PhD.

Major Public Health Concern 54 million Americans with osteoporosis or low BMD 2 million osteoporotic fractures each year Direct healthcare costs about $19 billion per year Increase is mortality, disability, loss of independence US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, Office of the Surgeon General; 2004. www.surgeongeneral.gov/library/bonehealth/. National Osteoporosis Foundation. www.nof.org. Accessed 01-01-2018.

Fracture Risk Assessment Will I end up like my mother? Intervention Thresholds Treatment Follow-up

WHO Classification of BMD T-score Normal -1.0 or higher Osteopenia Between -1.0 and -2.5 Osteoporosis -2.5 or lower Severe Osteoporosis -2.5 or lower + fragility fracture Applies to postmenopausal women and men age 50 and older. Cannot be used in premenopausal women and men under age 50. Should never be used in children (under age 20). T-score ≤ -2.5 is not always osteoporosis. A patient may have osteoporosis with a T-score > -2.5. WHO Study Group 1994. ISCD Official Positions.

NOF Treatment Guidelines For postmenopausal women and men age 50 and older, after appropriate evaluation for secondary causes Osteoporosis by T-score T-score -2.5 or less at FN, TH, or LS, or . . . Clinical Osteoporosis Hip or vertebral (clinical or morphometric) fracture, or . . . Low BMD + High Fx Risk T-score between -1.0 and -2.5 at FN, TH, or LS, and . . . FRAX 10-year probability of hip fracture ≥ 3% or major osteoporotic fracture ≥ 20% National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2014.

Medications for Osteoporosis Inhibit Bone Resorption (Antiresorptive) Stimulate Bone Formation (Anabolic) Alendronate (Fosamax, generic) Teriparatide (Forteo) Risedronate (Actonel, Atelvia, generic) Abaloparatide (Tymlos) Ibandronate (Boniva, generic) Zoledronate (Reclast, generic) Denosumab (Prolia) Raloxifene (Evista, generic) Salmon Calcitonin (Miacalcin, generic) Estrogen (various) CE/Baxedoxifene (Duavee)

Individualizing Initial Treatment Agent Comments Oral BPs Pro: inexpensive, work well in many patients Con: GI distress, avoid with low GFR, bad rep in lay press ZOL Pro: very long dosing interval, post-hip fracture data Con: acute phase reaction, avoid with low GFR, IV Dmab Pro: long dosing interval, greatest BMD increase, SC Con: FDA list of “side effects” (back pain, high cholesterol, etc.) TPT Pro: anabolic Con: high cost, daily injection, refrigeration, rat osteosarcoma Abalo Pro: anabolic, no refrigeration, less hypercalcemia than TPT Con: cost, daily injection, rat osteosarcoma RLX Pro: not a BP, decreases breast cancer risk Con: VTE, hot flashes, no proven hip fracture decrease Personal opinion.

Indications  Medication PMO GIO (Women, Men) Men Prevention Treatment Estrogen (many forms)  CE/BZA (Duavee) Raloxifene (Evista, generic) Alendronate (Fosamax, generic) Risedronate (Actonel, generic) Risedronate DR (Atelvia) Ibandronate PO (Boniva, generic) Ibandronate IV (Boniva) Zoledronate (Reclast, generic) Calcitonin IN (Miacalcin, generic) Denosumab (Prolia) Teriparatide (Forteo) Abalopartide (Tymlos) Paget’s dose: Fosamax 40 mg/day x 6 mo., Actonel 30 mg/day x 2 mo. Launch Dates: Fosamax 10/95, Miacalcin 1/96, Evista 1/98, Actonel 5/00, Weekly Fosamax 11/00

Fracture Risk Reduction in RCTs Medication Spine Nonvertebral Hip Estrogen (many forms)  CEE/BZA (Duavee) /  /- Raloxifene (Evista, generic)) - Alendronate (Fosamax, generic) Risedronate (Actonel, generic) Ibandronate (Boniva, generic) ( in post hoc analyses) Zoledronate (Reclast, generic) Calcitonin (Miacalcin, generic) Denosumab (Prolia) Teriparatide (Forteo) Abaloparatide (Tymlos)

A Brief History of Osteoporosis How did we get where we are today? E. Michael Lewiecki, MD Personal Opinion

Osteoporosis Care CRISIS Better Worse Then Now USA DXA Reimbursement Cuts (2007) WHI (2002) ONJ AFF Bureaucracy Media Reports FRAX Limited Time Fear of Side Effects Guidelines Competing Priorities More Marketing Drug Holidays Approval of More Drugs Calcium Competing Guidelines US Surgeon General’s Report Vitamin D Increasing Availability of DXA Risk Communication Bone Mass Measurement Act Treatment Gap Mass Marketing CRISIS Approval of Alendronate (1995) WHO Diagnostic Criteria (1994) DXA Introduced (1987)

Treatment Gap Getting Worse Review of US insurance claims data (commercial + Medicare) in 96,887 patients hospitalized with hip fracture, 2002-2011 Solomon DH et al. J Bone Miner Res. 2014;29:1929–1937.

Reduced Bisphosphonate Prescription Rates Starting in 2008 Jha S et al. J Bone Miner Res. 2015;30:2179-2187.

US Hip Fracture Trends 2002-2015 Hip Fracture Rates DXA Medicare Payments $139 Osteoporosis Diagnosis $82 $42 DXA Testing

Strategies to Reduce the Treatment Gap Public awareness / empowerment of patients Shared decision making Alignment of incentives More effective use of current treatments New drug development Harmonization of guidelines Fracture liaison services Better risk communication Restore DXA reimbursement Improve DXA quality Treat-to-target Sharing knowledge (Bone Health TeleECHO)

Can pharmacists help?

Survey of 1,222 Community Pharmacists in Canada Screening for Osteoporosis Screening for Risk of Falls Believed should be involved 47% 50% Actually were involved 17% 19% Barriers to providing these services Lack of time: 79% Lack of clinical tools: 65% Lack of coordination with other healthcare professionals: 55% Laliberte M-C et al. Osteoporos Int. 2013;24:1803-1815.

Systematic Review of Pharmacist Interventions for Osteoporosis Care 25 studies identified (3 RCTs) Interventions included patient counseling, education, QUS, and physician contact Results: interventions increased DXA testing and calcium intake in high risk patients Limitations: study bias, no study examined adherence to treatment, more and better designed studies are needed Elias MN et al. Osteoporos Int. 2011;22:2587-2596.

What You Can Do (If you have the interest, the time, and the resources) Identify patients who qualify for DXA testing Educate patients on long-term glucocorticoids on high risk of fracture Counsel on falls prevention, calcium, and vitamin D Distribute educational materials Inform on correct administration of oral BPs Advise fracture patients on risk of future fractures Communicate balance of benefits and risks Assess adherence to therapy Recognize the myths, understand the data, and appreciate the uncertainties in osteoporosis care

Controversies / Uncertainties Evaluation Treatment DXA Indications Testing intervals Quality Reimbursement Fracture risk assessment Wise use of FRAX Other algorithms Secondary causes Best w/u for a patient Non-pharmacological Best exercise Calcium and CV disease Target vitamin D level Pharmacological Initial drug selection How long to treat Changing therapy Combining therapy Benefit vs. risk

Indications for DXA Women age ≥ 65 and men age ≥ 70 Younger postmenopausal women, perimenopausal women, and men age 50-69 based on risk factor profile Adults with fragility fracture, disease or condition associated with low BMD or bone loss Extracted from NOF Clinician’s Guide to Prevention and Treatment of Osteoporosis and ISCD Official Positions, 2015.

There is no safe dose of prednisone High Fracture Risk with Any Dose UK General Practice Research Database 244,235 oral glucocorticoid users compared to 244,235 controls Prednisone: < 2.5 mg/day 2.5-7.5 mg/day ≥ 7.5 mg/day There is no safe dose of prednisone van Staa TP et al. J Bone Miner Res. 2000;15:993-1000.

From Osteoporosis Canada at http://www.osteoporosis.ca

From American Bone Health at https://americanbonehealth.org/

From National Osteoporosis Foundation at https://www.nof.org

“Calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) to the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults at this time.” Kopecky SL et al. Ann Intern Med. 2016;165(12):867-668.

Osteoporosis Wheel of Fear

Bisphosphonate Safety Issues Side Effects “Side Benefits” Short-term GI distress Acute phase reaction Hypocalcemia Renal toxicity Long-term Osteonecrosis of the jaw Atypical femur fractures Questionable Chronic musculo-skeletal pain Atrial fibrillation Esophageal cancer Impaired fracture healing Improved implant survival  risk of breast cancer  risk of endometrial cancer  risk of colorectal cancer  risk of stroke  risk of gastric cancer  risk of MI in RA patients  risk of type 2 DM  mortality Prieto-Alhambra D et al. Arthritis Rheum. 2014;66:3233-3240. Chlebowski RT et al. J Clin Oncol. 2010;28:3582-3590. Newcomb PA et al. J Clin Oncol. 2015;33:1186-1190. Dreyfuss JH. CA Cancer J Clin. 2010;60:343-344. Newcomb PA et al. Br J Cancer. 2010;102:799-802. Rennert G et al. J Clin Oncol. 2010;28:3577-3581. Vestergaard P et al. Calcif Tissue Int. 2011;88:255-262. Rennert G et al. J Clin Oncol. 2011;9:1146-1150. Kang JH et al. Osteoporos Int. 2012;23:2551-2557. Abrahamsen B et al. J Bone Miner Res. 2012;27:679-686. Center JR et al. J Clin Endocrinol Metab. 2011;96:1006-1014. Wolfe F et al. J Bone Miner Res. 2013;28:984-991. Konstantinos A et al. J Clin Endocrinol Metab. 2015;100:1933-1940. Sambrook PN et al. Osteoporos Int. 2011;22:2551-2556. Lee P et al. J Clin Endocrinol Metab. 2016;101:1945-1953.

Denosumab Safety Message to patients: “The most common side effects of Prolia® include back pain, pain in the arms and legs, high cholesterol, muscle pain, and bladder infections.” Adverse reactions in ≥ 2% of Patients with Osteoporosis and More Frequent Than with PBO Term Prolia (N=3886) PBO (N=3876) Back Pain 1347 (34.7%) 1340 (34.6%) Pain in extremity 453 (11.7%) 430 (11.1%) Hypercholesterolemia 280 (7.2%) 236 (6.1%) Myalgia 114 (2.9%) 94 (2.4%) Cystitis 228 (5.9%) 225 (5.8%) https://www.prolia.com/about/safety/ and package insert May 2017.

Osteonecrosis of the Jaw Ruggiero SL. J Oral Maxillofac Surg. 2004;62:527-534.

Atypical Femur Fractures Unadjusted and Age-adjusted Risk of AFF According to Duration of Bisphosphonate Therapy Years of Bisphosphonate Exposure Incidence of AFF per 100,000 person-years Atypical Femur Fracture Risk of AFF increases with duration of BP therapy (1). Risk of AFF is low in proportion to fractures prevented by BP therapy (1). After BP withdrawal, risk of AFF rapidly decreases by 70% per year (2). 1. Dell RM et al. J Bone Miner Res. 2012;27:2544–2550; 2. Schilcher J et al. N Engl J Med. 2011;364:1728-37.

10-Year Probabilities 80 year-old woman with FN T-score = -3.3 Includes 0.01% Atypical Femur Fracture Risk Includes 0.5% Atypical Femur Fracture Risk Untreated probability of major osteoporotic fracture calculated by FRAX. ONJ estimate is ~1/100,000 patient-treatment-years from ASBMR Task Force by Khosla S et al. J Bone Miner Res 2007;22:1479–149. AFF estimate untreated is ~0.01/10,000 and treated is ~5/10,000 patient-years from Schilcher J et al. N Engl J Med. 2011;364:1728-1737. Risk estimates assume long-term bisphosphonate therapy resulting in 50% reduction in fracture risk. MVA and murder data from the CDC at http://www.cdc.gov/nchs/data/nvsr/nvsr56/nvsr56_10.pdf. Image copyright © 2011 Lewiecki EM. Slide version.

Motor Vehicle Accidents Benefits and Risks Motor Vehicle Accidents Osteoporosis Wearing seat belts reduces the risk of serious crash-related injuries and deaths by about 50% Treatment with bisphosphonates reduces the risk of fractures by about 50% There are about 2.3 million adults treated in ERs each year for injuries from MVAs and about 2 million osteoporotic fractures each year. The risk of seat belt injuries and serious side effects from osteoporosis treatment is very small in proportion to the benefits. Data from multiple sources.

Myth: Osteoporosis Drugs Don’t Work After 5 Years Reality: The evidence supports anti-fracture efficacy for as long as 10 years in appropriately selected patients Uncertainty RCTs with a placebo group are typically 3 years for osteoporosis drugs No data beyond 10 years Studies with other drugs for chronic diseases are often far shorter, and we typically don’t know the long-term effects of any drugs for any disease

Drug Holiday Elective temporary withholding of bisphosphonate after at least 3-5 years in appropriate patients NOT “drug retirement” NOT “stopping treatment” NOT for non-bisphosphonates Rationale: persistence of anti-fracture benefit while possibly reducing long-term risks Very little data, many opinions Periodic reevaluation of balance of benefits and risks Adapted from Whitaker M et al. N Engl J Med. 2012;366:2048-2051. Black DM et al. N Engl J Med. 2012;366:2051-2053. Bonnick SL. J Clin Densitom. 2011;14:377-383. Watts NB et al. J Clin Endocrinol Metab. 2010;95:1555-1565.

Adler RA et al. J Bone Miner Res. 2016;31:16–35.

Postmenopausal Women Treated with Oral BP ≥ 5 Years or IV BP ≥ 3 Years Low fracture risk: hip T-score > -2.5 and no hip, spine, or multiple osteoporotic fracture before or during therapy Consider drug holiday of 2-3 years High fracture risk: hip T-score ≤ -2.5 or hip, spine, or multiple osteoporotic fracture before or during therapy Consider continuing oral BP up to 10 years and IV BP up to 6 years Adler RA et al. J Bone Miner Res. 2016;31:16–35.

No Holiday with Denosumab

Loss of Fracture Protection after Discontinuation of Denosumab Systematic review of literature on discontinuing Dmab Return of fracture risk to baseline after discontinuation and possible increase in risk of multiple VFs Stopping Dmab should be followed by alternative treatment Tsourdi E et al. ECTS Position Statement. Bone. 2017. Epub.

Sequencing with Anabolic Therapy Anabolic after potent BP (ALN) - delay or attenuation of anabolic effect Anabolic after Dmab - BMD decrease transient/sustained Anabolic after mild antiresorptive (ET, RIS) - expected onset of anabolic effect Antiresorptive after anabolic - essential

Bone Health

USA Participants: 21 Months Bone Health USA Participants: 21 Months 263 registered, 221 attended at least once, 35-50 attendees each week Other countries Canada Mexico Chile Brazil Trinidad and Tobago Ireland UK Lewiecki EM et al. ASBMR. 2017.

Self-Efficacy Outcomes Measures Bone Health Self-Efficacy Outcomes Measures Bone Health ECHO learners with direct patient care responsibilities who attended more than 10 clinics (n=10) Expert Very competent Competent Average Slight skills Vague skills No skills N/A After ECHO* Before ECHO Lewiecki EM et al. ASBMR. 2017. *P = 0.005 (very large effect size; Cohen and Sawilowsky)

Summary Osteoporosis is a common disease with serious consequences due to fractures Despite availability of effective and safe medications to reduce fracture risk, there is a large treatment gap We can do better