K Schleich Pharmacotherapy of Osteoporosis 2017 AUDIENCE

Pharmacotherapy
Kevin T. Schleich, PharmD, BCACP
of
Clinical Pharmacy Specialist, Department of Family Medicine
University of Iowa Hospitals and Clinics
Osteoporosis
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
Epidemiology
 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
www.iofbonehealth.org/epidemiology
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:

a) Normal bone density
b) Osteopenia
c) Osteoporosis
www.google.com/images/dxa_scan
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?
a) No change in therapy
b) Recommend increased dietary calcium and vitamin D
c) Recommend supplemental calcium and vitamin D
d) Recommend starting alendronate 70 mg weekly
e) 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.
FRAX Calculator
http://www.shef.ac.uk/FRAX/tool.aspx
Evaluating Osteopenia
Assess Risk
Non-Drug Therapy
Calcium + Vitamin D
Low-moderate Risk High-Risk

Postmenopausal women and men
• No history of fractures > 50 y.o. with:
• Osteopenia • Hip or vertebral fracture
• FRAX <3% risk hip fx • Osteoporosis
• FRAX <20% risk of major • Osteopenia
osteoporosis-related fx • FRAX > 3% risk hip fx
• FRAX > 20% risk of major
osteoporosis-related fx
+/- Drug Therapy Drug Therapy

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
Calcium Intake
 What is an adequate amount of calcium (combination of dietary
and supplemental) to recommend for EP?
a. 2000 mg
b. 1500 mg
c. 1000 mg
d. 500 mg
 NOF recommends __________ mg/day of total intake

 Milk, yogurt, cheese, fortified foods/juices (~100-300 mg/serving)
 Amounts in excess of _____ mg/day have limited benefit and

may increase risk:
 Kidney stones
 Cardiovascular risk
Calcium Supplementation
 Two different formulations of calcium
Carbonate Citrate
• Less expensive • More expensive

• Requires acidic environment • Can be taken without regard
for absorption (take with to food
food) • Required form if patient is on
a proton pump inhibitor (PPI)
www.google.com/images/calcium_carbonate
www.google.com/images/calcium_citrate
Vitamin D Intake
 What is an adequate amount of vitamin D supplementation to
recommend for EP?
a. 400 IU daily
b. 1000 IU daily
c. 4000 IU daily
d. 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: 30-60 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
1. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013.
2. "IOM Home - Institute of Medicine." IOM Home. Web. 12 Mar. 2012. <http://www.iom.edu>.
3. BMJ 2009;339:b3692 (doi: 10.1136/bmj.b3692)
Evaluating Osteopenia
Assess Risk
Non-Drug Therapy
Calcium + Vitamin D
Low-moderate Risk High-Risk

Postmenopausal women and men
• No history of fractures > 50 y.o. with:
• Osteopenia • Hip or vertebral fracture
• FRAX <20% risk of major • Osteoporosis
osteoporosis-related fx • Osteopenia
• FRAX <3% risk hip fx • FRAX > 20% risk of major
osteoporosis-related fx
• FRAX > 3% risk hip fx
Likely Avoid Drug Drug Therapy

Therapy
Drugs
www.google.com/raining_pills
Osteoporosis Therapy
FDA-Approved Treatment of FDA-Approved Prevention of
Osteoporosis Osteoporosis
• Bisphosphonates
• Denosumab • Bisphosphonates
• Teriparatide • Denosumab
• Raloxifene • Raloxifene
• Calcitonin • Estrogen/Hormone
• Estrogen/Hormone Therapy
Therapy
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
Osteoclast Pac-Man
 Contraindications
 Orally: Esophageal abnormalities (GERD/PUD)
 Orally: Inability to sit/stand for 30-60 minutes
 CrCl < 30 mL/min (ibandronate, risedronate)
 CrCl < 35 mL/min (alendronate, zoledronic acid)
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. 2012. <http://www.ncbi.nlm.nih.gov/pubmed/14640924>.
Alendronate [package insert]. Merck Sharp & Dohme Corp. Whitehouse Station, NJ. 2012.
Ibandronate [package insert]. Genentech USA, Inc. South San Francisco, CA. 2011.
Risedronate [package insert]. Warner Chilcott, LLC. Rockaway, NJ. 2011.
Zoledronic acid [package insert]. Novartis Pharmaceuticals Corporation. East Hanover, NJ. 2011.
Bisphosphonate Therapy
Medication Dosage Forms Prevention Dose Treatment Dose
Tablet
• 5, 10, 35, 70 mg
• + Vitamin D (2800 mg 10 mg daily
Alendronate or 5600 mg/week) 5 mg daily
(Fosamax®, Fosamax® + D, Effervescent tablet 35 mg weekly 70 mg weekly +/-
Binosto®)
• 70 mg vitamin D
Oral Solution
• 70 mg/75 mL
Tablet 5 mg daily
Risedronate • 5, 35, 75, 150 mg 35 mg weekly
(Actonel®, Atelvia®) 75 mg x 2 consecutive days monthly
150 mg monthly
Ibandronate Tablet – 150 mg
150 mg tab monthly
150 mg tab monthly
(Boniva®) IV Soln – 1 mg/mL 3 mg IV every 3 months
Zoledronic acid IV Soln – 5 mg/100 mL 5 mg every 2 years 5 mg every year
(Reclast®)
Bisphosphonate Pearls
Oral Tablets IV Solutions
Check calcium and vitamin D levels before starting therapy
• Take on empty stomach first thing Ibandronate (Boniva®)
in the AM with 8 oz. of plain water
• Given over 15-30 seconds every 3
months
• Must stay upright/nothing PO for at
least 30 minutes after each dose • Check serum creatinine prior to
each infusion
(60 minutes for ibandronate)
Zoledronic Acid (Reclast®)
• Assess ability to swallow tablets • Administered over at least 15 min
• Check serum creatinine prior to
each infusion
• Recommend dental exam prior to • Pre-treat with acetaminophen to
initiating therapy
avoid acute phase reaction
Bisphosphonate Hot Topics
 Atypical Fractures
 Long-term bisphosphonate therapy
may reduce normal physiological bone
turnover/repair
http://www.internalmedicinenews.com
 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
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation;
2013.
Ther Adv Chronc Dis. 2015 Jul;6(4):185-93
 Osteonecrosis of the Jaw (ONJ)
 Clinically presents as an area of exposed
bone in the mandible, maxilla or palate
http://thesmilejournal.com
 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

National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation;
2013.
 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.
a) Indefinitely
b) Another 2 years, at which time we can recheck a DXA
c) Another 8 years, at which time we can recheck a DXA
d) Stop today and check a DXA to obtain a new baseline
J Bone Miner Res 2016 Jan;31(1):16-35.

Denosumab (Prolia ) ®
 Mechanism
 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. 2012.
 Adverse Effects
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. 2012.
 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
J Clin Endocrinol Metab. 2011 Apr;96(4):972-80.
J Clin Endocrinol Metab. 2016 Oct 12:jc20163170
PTH (1-34), teriparatide
(Forteo®)
 Dose
 20 mcg subcutaneous injection daily
 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
Teriparatide [package insert]. Eli Lilly and Company, Indianapolis, IN. 2009.
Raloxifene (Evista ) ®
 Dose
 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
Raloxifene [package insert]. Eli Lilly and Company, Indianapolis, IN. 2007.
Calcitonin
 Available Dosage Forms
 Nasal spray – 200 IU/actuation
 Generic, Fortical®, Miacalcin®
 Injectable solution – 200 IU/mL
 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
Calcitonin salmon nasal spray [package insert]. Novartis Pharmaceuticals, East Hanover, NJ. 2014
Other Therapy
 Estrogen 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
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
Year 1 Year 2
Double-blinded Open labeled
All patients received
3591 placebo denosumab every 6
injection every month
months
7180
postmenopausal women Daily calcium 500-1000 mg + vitamin D 600-800 IU
(T-score -2.5 to -3.5)
enrolled All patients received
3589 romosozumab denosumab every 6
injection every month
months
 Primary endpoints: cumulative incidence of vertebral fractures at 12 and 24

months
 Secondary endpoints: clinical and non vertebral fractures

N Engl J Med. 2016 Oct 20;375(16)
Future of Osteoporosis Treatment?
Relative Risk Absolute Number
Romosozumab Placebo Risk Needed to
Reduction Reduction Treat
Vertebral 16/3321 59/3322 73%
fracture (0.5%) (1.8%) (p<0.001)
1.2% 77
Year 1 Clinical 58/3589 90/3591 36% 112
fracture (1.6%) (2.5%) (p=0.008) 0.8%
Non
vertebral 56/3589 75/3591 P=0.10 N/A N/A
fracture (1.6%) (2.1%)
Vertebral 21/3325 84/3327 75%

Year 2 fracture (0.6%) (2.5%)
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)
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
www.google.com/images
Kevin T. Schleich, Pharm.D., BCACP
Clinical Pharmacy Specialist, Department of Family Medicine
University of Iowa Hospitals and Clinics
kevin-schleich@uiowa.edu
www.hawkeyesports.com

K Schleich Pharmacotherapy of Osteoporosis 2017 AUDIENCE

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Pharmacotherapy

Kevin T. Schleich, PharmD, BCACP

 Discuss the appropriate amounts of calcium and vitamin D for

 Focus on mainstays of bisphosphonate therapy including:

 Review non-bisphosphonate therapies for osteoporosis,

 EP should be classified as having:

 How should we approach further treatment for EP now

Low-moderate Risk High-Risk

+/- Drug Therapy Drug Therapy

 Avoidance of Tobacco/Excessive Caffeine

 Avoidance of Excessive Alcohol Intake

 NOF recommends __________ mg/day of total intake

 Amounts in excess of _____ mg/day have limited benefit and

• Less expensive • More expensive

 NOF recommends ________international units (IU)/day

Low-moderate Risk High-Risk

Likely Avoid Drug Drug Therapy

 Very rare occurrences of atypical fracture sites (femoral

 Concomitant glucocorticoid therapy appears to place

 Initially there were rare reports of ONJ occurring in cancer

 Subsequent rare reports of ONJ occurred with both oral and IV

 Factors that may increase susceptibility

 Recommend good oral hygiene

J Bone Miner Res 2016 Jan;31(1):16-35.

 Available Dosage Form

 Rebound Vertebral Fractures

 8 of 9 patients had numerous fractures

 8 of 9 patients had osteoporosis

 Fractures occurred within 3-16 months

 Impact on fracture rates is unknown

 Not recommended at this time

 Primary endpoints: cumulative incidence of vertebral fractures at 12 and 24

 Secondary endpoints: clinical and non vertebral fractures

Vertebral 21/3325 84/3327 75%

 Bone mineral density in the spine increased by 13% in the romosozumab

 May end up being another option in the treatment of postmenopausal

 Bisphosphonates remain the cornerstone of therapy for the

 Consider appropriate duration of therapy with bisphosphonates and

 The risk of developing an osteoporotic fracture far outweighs the risk

 Continue to watch for emerging drug therapies for the treatment of

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