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Pharmacotherapy of Osteoporosis

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1 Pharmacotherapy of Osteoporosis
Kevin T. Schleich, PharmD, BCACP Clinical Pharmacy Specialist, Department of Family Medicine University of Iowa Hospitals and Clinics

2 Objectives Briefly review the diagnostic criteria for osteoporosis/ osteopenia Discuss the appropriate amounts of calcium and vitamin D for treatment/prevention of osteoporosis and osteopenia Focus on mainstays of bisphosphonate therapy including: Comparison of available drugs Risks vs. benefits of long-term therapy Comparative incidence of rare adverse effects Drug holidays Review non-bisphosphonate therapies for osteoporosis, including newer agents

3 Epidemiology Recurrence Morbidity/Mortality Incidence
Almost 9 million new osteoporotic fractures annually 1 every 3 seconds 1 in every 3 women and 1 in every 5 men will have an osteoporotic fracture Recurrence Of those who have previously had an osteoporotic fracture, ~85% will have a subsequent fracture Morbidity/Mortality ~25% 1-year mortality following a hip fracture ~33% of patients require long-term care placement following a hip fracture

4 Warm-up EP is a 62 year-old post menopausal woman with no significant medical history who requests a DXA scan at her annual exam. It reveals the following T-scores: Left femoral neck: -1.9 Left hip: -0.4 Lumbar spine: -0.9 EP should be classified as having: Normal bone density Osteopenia Osteoporosis

5 Definitions Osteopenia: T-score between ___ and ___
Osteoporosis: T-score < ___ How should we approach further treatment for EP now that she has been diagnosed with osteopenia? No change in therapy Recommend increased dietary calcium and vitamin D Recommend supplemental calcium and vitamin D Recommend starting alendronate 70 mg weekly I need more information before I do any more doctoring National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013.

6 FRAX Calculator When entering T-scores, it states that T scores are based on the NHANES reference values for women aged years. The same absolute values are used in men. Therefore, you will get much more accurate results if you actually know the device used and the actual bone density.

7 Evaluating Osteopenia
Assess Risk Non-Drug Therapy Calcium + Vitamin D Low-moderate Risk No history of fractures Osteopenia FRAX <3% risk hip fx FRAX <20% risk of major osteoporosis-related fx High-Risk Postmenopausal women and men > 50 y.o. with: Hip or vertebral fracture Osteoporosis Osteopenia FRAX > 3% risk hip fx FRAX > 20% risk of major osteoporosis-related fx +/- Drug Therapy Drug Therapy

8 Non-Drug Therapy Regular Weight-Bearing Exercise (walking, jogging, lifting) Reduces the risk of falls and fractures May modestly increase bone density Benefits are lost when no longer exercising Fall Prevention Avoiding drugs that increase the risk of falls, environmental Avoidance of Tobacco/Excessive Caffeine Avoidance of Excessive Alcohol Intake > 3 drinks per day is detrimental to bone health Also increases the risk of falling National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013.

9 Calcium Intake What is an adequate amount of calcium (combination of dietary and supplemental) to recommend for EP? 2000 mg 1500 mg 1000 mg 500 mg NOF recommends __________ mg/day of total intake Milk, yogurt, cheese, fortified foods/juices (~ mg/serving) Amounts in excess of _____ mg/day have limited benefit and may increase risk: Kidney stones Cardiovascular risk National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013.

10 Calcium Supplementation
Two different formulations of calcium Carbonate Citrate Less expensive Requires acidic environment for absorption (take with food) More expensive Can be taken without regard to food Required form if patient is on a proton pump inhibitor (PPI)

11 Vitamin D Intake NOF recommends ________international units (IU)/day
What is an adequate amount of vitamin D supplementation to recommend for EP? 400 IU daily 1000 IU daily 4000 IU daily 50,000 IU daily NOF recommends ________international units (IU)/day Essential for calcium absorption, bone health, muscle performance, and balance 20% RRR in fracture and 12% RRR in falls Goal range: ng/mL Most recent (2010) IOM update states that the safe upper limit of vitamin D is 4000 IU/day Some studies suggest that amounts up to 10,000 IU/day are safe for most individuals National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. "IOM Home - Institute of Medicine." IOM Home. Web. 12 Mar < BMJ 2009;339:b3692 (doi: /bmj.b3692)

12 Evaluating Osteopenia
Assess Risk Non-Drug Therapy Calcium + Vitamin D Low-moderate Risk No history of fractures Osteopenia FRAX <20% risk of major osteoporosis-related fx FRAX <3% risk hip fx High-Risk Postmenopausal women and men > 50 y.o. with: Hip or vertebral fracture Osteoporosis Osteopenia FRAX > 20% risk of major osteoporosis-related fx FRAX > 3% risk hip fx Likely Avoid Drug Therapy Drug Therapy

13 Drugs

14 Osteoporosis Therapy FDA-Approved Treatment of Osteoporosis
FDA-Approved Prevention of Osteoporosis Bisphosphonates Denosumab Teriparatide Raloxifene Calcitonin Estrogen/Hormone Therapy Bisphosphonates Denosumab Raloxifene Estrogen/Hormone Therapy

15 Bisphosphonate Therapy
Mechanism of Action Inhibition of osteoclast-mediated bone resorption Adverse Effects Common: GI (n/v/d, abdominal pain, constipation), headache, fever Serious: esophageal damage, gastric ulcer, osteonecrosis of jaw, atypical femur fracture Contraindications Orally: Esophageal abnormalities (GERD/PUD) Orally: Inability to sit/stand for minutes CrCl < 30 mL/min (ibandronate, risedronate) CrCl < 35 mL/min (alendronate, zoledronic acid) Osteoclast Pac-Man Miller, Paul. “Efficacy and Safety of Long-term Bisphosphonates in Postmenopausal Osteoporosis.” National Center for Biotechnology Information. U.S. National Library of Medicine. Web. 29 Feb < Alendronate [package insert]. Merck Sharp & Dohme Corp. Whitehouse Station, NJ Ibandronate [package insert]. Genentech USA, Inc. South San Francisco, CA Risedronate [package insert]. Warner Chilcott, LLC. Rockaway, NJ Zoledronic acid [package insert]. Novartis Pharmaceuticals Corporation. East Hanover, NJ

16 Bisphosphonate Therapy
Medication Dosage Forms Prevention Dose Treatment Dose Alendronate (Fosamax®, Fosamax® + D, Binosto®) Tablet • 5, 10, 35, 70 mg • + Vitamin D (2800 mg or 5600 mg/week) Effervescent tablet • 70 mg Oral Solution • 70 mg/75 mL 5 mg daily 35 mg weekly 10 mg daily 70 mg weekly +/- vitamin D Risedronate (Actonel®, Atelvia®) • 5, 35, 75, 150 mg 75 mg x 2 consecutive days monthly 150 mg monthly Ibandronate (Boniva®) Tablet – 150 mg IV Soln – 1 mg/mL 150 mg tab monthly 3 mg IV every 3 months Zoledronic acid (Reclast®) IV Soln – 5 mg/100 mL 5 mg every 2 years 5 mg every year National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. Alendronate [package insert]. Merck Sharp & Dohme Corp. Whitehouse Station, NJ Ibandronate [package insert]. Genentech USA, Inc. South San Francisco, CA Risedronate [package insert]. Warner Chilcott, LLC. Rockaway, NJ Zoledronic acid [package insert]. Novartis Pharmaceuticals Corporation. East Hanover, NJ

17 Bisphosphonate Pearls
Oral Tablets IV Solutions Check calcium and vitamin D levels before starting therapy Take on empty stomach first thing in the AM with 8 oz. of plain water Must stay upright/nothing PO for at least 30 minutes after each dose (60 minutes for ibandronate) Assess ability to swallow tablets Recommend dental exam prior to initiating therapy Ibandronate (Boniva®) Given over seconds every 3 months Check serum creatinine prior to each infusion Zoledronic Acid (Reclast®) Administered over at least 15 min Pre-treat with acetaminophen to avoid acute phase reaction National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. Alendronate [package insert]. Merck Sharp & Dohme Corp. Whitehouse Station, NJ Ibandronate [package insert]. Genentech USA, Inc. South San Francisco, CA Risedronate [package insert]. Warner Chilcott, LLC. Rockaway, NJ Zoledronic acid [package insert]. Novartis Pharmaceuticals Corporation. East Hanover, NJ

18 Bisphosphonate Hot Topics
Atypical Fractures Long-term bisphosphonate therapy may reduce normal physiological bone turnover/repair Very rare occurrences of atypical fracture sites (femoral shaft, pubic bone) in women taking alendronate 7-year cohort study with ~53,000 women treated for at least 5 years with a bisphosphonate Atypical fracture occurred in 185 patients (~0.35%) within 2 years of stopping the bisphosphonate Concomitant glucocorticoid therapy appears to place women at higher risk Thinking of the fact that 1 in 3 women will have an osteoporotic fracture means that you are 100 x more likely to have an osteoporotic fracture than an atypical femur fracture. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. Ther Adv Chronc Dis Jul;6(4):185-93

19 Bisphosphonate Hot Topics
Osteonecrosis of the Jaw (ONJ) Clinically presents as an area of exposed bone in the mandible, maxilla or palate Initially there were rare reports of ONJ occurring in cancer patients treated only with high-dose IV bisphosphonates Subsequent rare reports of ONJ occurred with both oral and IV bisphosphonates used for osteoporosis IV remains much more common Factors that may increase susceptibility Age > 50, female, previous invasive dental work Recommend good oral hygiene 0.26 cases per 1000 people years… = 0.026% therefore like 1000 x more likely to have an osteoporotic fracture than this National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013.

20 Bisphosphonate Hot Topics
TJ is a 72 year-old female with who has been on zoledronic acid 5 mg every 12 months for the past 3 years when she was diagnosed with osteoporosis (femoral neck T-score at time of diagnosis -2.6). How long should Ms. J remain on the bisphosphonate? She has no other significant personal or family medical history. Indefinitely Another 2 years, at which time we can recheck a DXA Another 8 years, at which time we can recheck a DXA Stop today and check a DXA to obtain a new baseline J Bone Miner Res 2016 Jan;31(1):16-35. 

21 Denosumab (Prolia®) Mechanism Available Dosage Form Dose
Receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor Inhibits the formation, function and survival of osteoclasts Available Dosage Form 60 mg/mL injectable solution Dose 60 mg SubQ as a single dose every 6 months in physician’s office May be an option for patients with impaired renal function because no adjustment necessary for renal insufficiency Denosumab [package insert]. Amgen Manufacturing Limited, Thousand Oaks, CA

22 Denosumab (Prolia®) Adverse Effects Monitoring Counseling Pearls
Hypocalcemia, hypophosphatemia, GI upset, arthralgia/back ache, headache, increased risk of infection, ONJ, atypical fracture Monitoring Calcium, phosphorus and magnesium Bone mineral density Counseling Pearls Must be kept in refrigerator until prior to injection Remove from refrigerator ~15-30 minutes prior to injection Patient must take supplemental calcium and vitamin D to maintain adequate serum calcium levels during therapy Positive effects rapidly reversed after discontinuation Denosumab [package insert]. Amgen Manufacturing Limited, Thousand Oaks, CA

23 Denosumab (Prolia®) Rebound Vertebral Fractures
Discontinuation Effects After 2 years of treatment with denosumab, bone turnover rate increased again within 3 months BMD declined to pre-treatment levels within 2 years Rebound Vertebral Fractures Nine cases of female patients having vertebral fractures after d/c denosumab 8 of 9 patients had numerous fractures (mean = 5.5 fractures) 8 of 9 patients had osteoporosis Fractures occurred within 3-16 months after denosumab discontinuation May consider initiating alternative therapy after discontinuing denosumab J Clin Endocrinol Metab. 2011 Apr;96(4): J Clin Endocrinol Metab. 2016 Oct 12:jc

24 PTH (1-34), teriparatide (Forteo®)
Dose 20 mcg subcutaneous injection daily Mechanism of Action Recombinant formulation of endogenous PTH Stimulates osteoblast function, increases gastrointestinal calcium absorption, and increases renal tubular reabsorption of calcium  increased bone mineral density, bone mass, and strength Only drug available that can stimulate new bone formation Place in Therapy For patients with very low BMD (T-score < -3.0) Can be used for two years to promote new bone formation then switch to a bisphosphonate ~$1200/month $29,000 per course of therapy Some reports of use in sports med world for stress fractures. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. Teriparatide [package insert]. Eli Lilly and Company, Indianapolis, IN

25 Raloxifene (Evista®) Dose Adverse Effects Place in Therapy
60 mg tablet daily Adverse Effects Increased risk of DVT, increased incidence of hot flashes Place in Therapy Used in postmenopausal women with osteoporosis at high-risk of breast cancer who have an indication for breast cancer prophylaxis National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. Raloxifene [package insert]. Eli Lilly and Company, Indianapolis, IN

26 Calcitonin Available Dosage Forms Mechanism of Action Dose
Nasal spray – 200 IU/actuation Generic, Fortical®, Miacalcin® Injectable solution – 200 IU/mL Mechanism of Action Reduces the number of osteoclasts prevents resorptive activity of the bone  reduced bone turnover rate Temporarily improves bone formation by increasing osteoblastic activity Only been shown to be effective in reducing subsequent vertebral fractures by 30% in those with a prior vertebral fracture Dose Nasal spray – 1 spray intranasally, alternating nostrils daily Injection – 100 IU (0.5 mL) SUBQ or IM every other day Adverse Effects Nasal – rhinitis, epistaxis (rare) Injection – injection site reaction, flushing of hands/face, nausea National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. Calcitonin salmon nasal spray [package insert]. Novartis Pharmaceuticals, East Hanover, NJ. 2014

27 Other Therapy Estrogen Therapy Combination Therapy
No longer recommended for osteoporosis prevention Combination Therapy Can provide additional small increase in bone mineral density compared to monotherapy Impact on fracture rates is unknown Not recommended at this time National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013.

28 Future of Osteoporosis Treatment?
Romosozumab: monoclonal antibody that blocks sclerostin Sclerostin is a protein that inhibits bone formation Sclerostin mutations have been linked to skeletal overgrowth syndromes Primary endpoints: cumulative incidence of vertebral fractures at 12 and 24 months Secondary endpoints: clinical and non vertebral fractures Year 1 Double-blinded Year 2 Open labeled 3591 placebo injection every month All patients received denosumab every 6 months 7180 postmenopausal women (T-score -2.5 to -3.5) enrolled Daily calcium mg + vitamin D IU All patients received denosumab every 6 months SubQ injection Clinical fractures were a composite of nonvertebral and symptomatic vertebral fractures. 3589 romosozumab injection every month N Engl J Med. 2016 Oct 20;375(16)

29 Future of Osteoporosis Treatment?
Year 1 Romosozumab Placebo Relative Risk Reduction Absolute Risk Reduction Number Needed to Treat Vertebral fracture 16/3321 (0.5%) 59/3322 (1.8%) 73% (p<0.001) Clinical fracture 58/3589 (1.6%) 90/3591 (2.5%) 36% (p=0.008) Non vertebral fracture 56/3589 75/3591 (2.1%) P=0.10 N/A Year 2 21/3325 (0.6%) 84/3327 75% 1.2% 77 0.8% 112 1.8% 52 Bone mineral density in the spine increased by 13% in the romosozumab group May end up being another option in the treatment of postmenopausal osteoporosis N Engl J Med. 2016 Oct 20;375(16)

30 Summary Ensure that patients with osteoporosis/osteopenia have sufficient amounts of dietary/supplemental calcium and vitamin D Bisphosphonates remain the cornerstone of therapy for the prevention and treatment of osteoporosis Denosumab offers an alternative, which may be especially attractive in patients with renal insufficiency Consider appropriate duration of therapy with bisphosphonates and recommend a drug holiday if appropriate The risk of developing an osteoporotic fracture far outweighs the risk of developing rare adverse effects Continue to watch for emerging drug therapies for the treatment of osteoporosis

31

32 THANK YOU! Kevin T. Schleich, Pharm.D., BCACP
Clinical Pharmacy Specialist, Department of Family Medicine University of Iowa Hospitals and Clinics


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