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

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