Transcript Planning Committee • Cheryl Lambing, MD, Co-Chair UCLA / Ventura County Medical Center • Marjorie Luckey, MD, Co-Chair Saint Barnabas Medical Center • Steven T.

Planning Committee
• Cheryl Lambing, MD, Co-Chair
UCLA / Ventura County Medical Center
• Marjorie Luckey, MD, Co-Chair
Saint Barnabas Medical Center
• Steven T. Harris, MD
University of California, San Francisco
• Pamela Kushner, MD
University of California, Irvine
• Diane L. Schneider, MD, MSc
University of California, San Diego
Learning Objectives
• Identify patients at high risk for osteoporotic
fracture
• Individualize risk assessment including use of the
WHO FRAX® tool
• Discuss general measures to optimize calcium,
vitamin D, and exercise
• Evaluate the different pharmacologic therapies to
match the patient’s clinical situation
• Utilize different modalities to improve adherence
and compliance with treatment plan
Osteoporosis
• Systemic skeletal disorder of compromised bone strength
increased risk of fracture
– 34 million Americans: low bone mass
– 10 million Americans: osteoporosis
• 1 in 2 women and 1 in 4 men >age 50 will have an
osteoporosis-related fracture in their lifetime
• By 2020, 1 in 2 Americans >age 50 will be at risk for
fractures from osteoporosis or low bone mass
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. Available at:
http://www.surgeongeneral.gov/library/reports/bonehealth/full_report.pdf. Accessed September 13, 2013.
Fracture Facts!
• 2 million bone breaks a year (“2 million 2 many”)1
• Only 2 in 10 patients with osteoporosis get a follow-up test or
treatment for osteoporosis1
• Fractures may have serious consequences2
– Hip fracture
• 10%-20% additional mortality per year
• 20% of hip fracture patients require long-term nursing home care
• Only 40% fully regain their pre-fracture level of independence1
1. National Bone Health Alliance. 2 Million 2 Many. Available at: http://www.2million2many.org/. Accessed September 13,
2013. 2. 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. Available
at: http://www.surgeongeneral.gov/library/reports/bonehealth/full_report.pdf. Accessed September 13, 2013.
Underdiagnosed and
Undertreated
• Underdiagnosed: National Osteoporosis Risk Assessment
(NORA) study (200,160 postmenopausal women)1
– 40% osteopenic
– 7% osteoporotic
– 11% ≥1 fracture after age 45 years
• Undertreated: women meeting criteria for treatment2
–
–
–
–
15.7% not taking calcium
18.6% not taking vitamin D
52.7% not exercising >2 hrs per week
35.3% not receiving therapy
1. Siris ES, et al. JAMA. 2001;286:2815-2822.
2. Schnatz PF, et al. Menopause. 2011;18:1072-1078.
The Clinical Challenge
• Often asymptomatic1
– Until fracture occurs1
– Even after some fractures (eg, 2/3 of
vertebral fractures are asymptomatic)2
• The challenge to clinicians1:
– Identify patients at high risk for fracture
– Prevent first fracture
1. South-Paul JE. Am Fam Physician. 2001;63:1121-1128.
2. Lenchnik L, et al. AJR. 2004;183:949-958.
Sharon
• 62-year-old White female
• 5′4″; 150 lbs
• 10 years postmenopause
• DXA performed 4 years ago
– Spine T-score: -2.1
– Right hip T-score (of neck): -1.6
Personal History - Sharon
• Her mother suffered hip fracture in her 70s
• Performs weight-bearing exercise 3 times
per week
• Nonsmoker
• Rarely drinks alcohol
• Takes 1 calcium supplement each day –
unknown dose
• Consumes no dairy products and no
vitamin D
Sharon
Worried because of
family history —
What is the next step?
Optimizing Fracture Prevention
in Primary Care
• Identifying patients at high risk
• Individualized risk assessment
• Management strategies
– Nonpharmacologic modalities
– Pharmacologic therapy
– Modalities to improve adherence and compliance
The Good News
• Excellent diagnostic tools
– Bone densitometry with DXA –
noninvasive test
– FRAX® – new tool to help with management
decisions in patients with reduced bone
mineral density
• Effective and safe treatments
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National
Osteoporosis Foundation; 2013. Available at: http://www.nof.org/hcp/clinicians-guide. Accessed September 13, 2013.
Relative Risk
of Hip Fracture
Strong Relationship Between
Bone Density and Bone Strength
30
20
10
0
-5
-4
-3
-2
-1
0
T-score
• Bone density accounts for 60% to 80%
of bone strength in untreated patients1
• Best early predictor of fracture risk2
• Permits diagnosis before fractures
1.
2.
Kushida K. Clin Calcium. 2004;14:11-17.
Fogelman J, Blake GM. J Nucl Med. 2000;41:2015-2025.
Age Is a Major Risk Factor
for Fracture
AGE
10-Year Probability of
Symptomatic Fracture (%)
80
70
Age 70
T-score -2.5
24% Fx Risk
60
50
Age 50
T-score -2.5
12% Fx Risk
-3
-2
-1
With kind permission from Springer Science+Business Media: Kanis JA ,et al. Ten year probabilities of osteoporotic
fractures according to BMD and diagnostic thresholds. Osteoporos Int.2001;12:989-995. Adapted from Fig. 3. ©
2001 International Osteoporosis Foundation and National Osteoporosis Foundation.
2010 Guidelines for Bone Density Testing
• Screening
–
–
All women age 65 and older1,2
All men age 70 and older1
• Test postmenopausal women and men >50 if1:
–
–
–
Fracture after age 50
Clinical risk factors for osteoporosis
Conditions/medications associated with bone loss
o
o
COPD, RA, hyperparathyroidism, celiac disease, IBD
Oral glucocorticoids, anticonvulsants, proton pump
inhibitors, SSRIs, aromatase inhibitors
1. Adapted from National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis.
Washington, DC: National Osteoporosis Foundation; 2013. Available at: http://www.nof.org/hcp/clinicians-guide. Accessed
September 13, 2013.
2. US Preventive Services Task Force. Ann Intern Med. 2002;137:526-528.
Majority of Fractures Occur in Patients
With Osteopenia, Not Osteoporosis!
Why?
• Osteopenia patients outnumber those with osteoporosis
3:1
• Fracture risk—determined by more than just BMD
• Clinical factors such as age, lifestyle, and family and
personal medical history also play a role
Implications
• Appropriate treatment depends on being able to
accurately determine the risk of future fractures
Davey DA. S Afr Med J. 2012;102:285-288.
NOF Guidelines 2010:
Whom to Treat
After exclusion of secondary causes,
treat postmenopausal women and men
age 50 and older who have…
Osteoporosis
Clinical diagnosis:
Hip or spine fracture
DXA diagnosis:
T-score -2.5 or below
in the spine or hip
T-scores between
-1.0 and -2.5 and
10-year risk of fractures:
≥3% for hip fracture
or
≥20% for a major osteoporotic fracture
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National
Osteoporosis Foundation; 2013. Available at: http://www.nof.org/hcp/clinicians-guide. Accessed September 13, 2013.
FRAX®
• Statistically robust fracture risk prediction tool developed
by the WHO for world-wide use
• Combines BMD + clinical risk factors to predict fracture
risk better than either alone
• Predicts the 10-year probability of major osteoporotic
fracture
– Hip, spine, wrist, or humerus
• Use when the decision to treat is uncertain
WHO FRAX® Tool. http://www.shef.ac.uk/FRAX/. Accessed September 13, 2013.
Answering Risk Factor
Questions in FRAX®
Prior fracture
Denotes a previous adult fracture after age 40
occurring with little or no trauma – fractures of face,
fingers, toes excluded1
Systemic corticosteroids
Best applies to current or long-term past use of
oral steroids (≥5 mg/day prednisone equivalent
for ≥3 months)1,2
1.
2.
1. National Osteoporosis Foundation. FRAX® Implementation Guide. Available at: http://www.iscd.org/wpcontent/uploads/2012/10/FRAXImplementationGuide_000.pdf . Accessed September 13, 2013.
2. Kanis J, et al. Osteoporosis Int. 2005;16:581-589.
FRAX® Caveats:
Entering Bone Density Data
Use Femoral Neck Bone
Mineral Density (BMD) only
Select DXA manufacturer and enter BMD (g/cm2)
NOF Guidelines:
≥20% major fx
≥3% hip fx
Benefits of FRAX®
• Treatment decisions in osteopenic patients clearer
– Decision is based on the risk of fracture, not T-score
alone
• Identifies patients at high-risk for fractures to ensure that
they are offered treatment to lower their risk
• Helps avoid giving medication to those who are at low
risk and have little to gain from treatment
“Specific treatment decisions must be individualized”
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC:
National Osteoporosis Foundation; 2013. Available at: http://www.nof.org/hcp/clinicians-guide. Accessed September 13,
2013.
When Clinical Judgment
Is Needed
FRAX® may underestimate fracture risk:
• Some risk factors (glucocorticoids, smoking, alcohol,
fractures) are dose dependent, but FRAX® can’t
consider dose
• Some risk factors that increase the risk of fractures
independently of their effect on BMD are not included
in FRAX®:
– Falls
– Frailty
– Some diseases and medications (immobilization, diabetes,
anticonvulsants, SSRIs, PPIs, TZDs)
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC:
National Osteoporosis Foundation; 2013. Available at: http://www.nof.org/hcp/clinicians-guide . Accessed September 13,
2013; Gnudi S, et al. J Bone Miner Res. 2001;16:1130-1135; Nguyen TV, et al. J Bone Miner Res. 2005;20:1195-1201;
Sornay-Rendu E, et al. J Bone Miner Res. 2005;20:1929-1935.
Be on the Lookout for Silent Fractures
• 65-year-old, T-score -1.6
• Height measurement: 2.5″ loss from her young adult
height; lateral spine x-ray ordered
Vertebral Fractures:
• 2/3 unrecognized by patients/clinicians
• Indicate very high risk for future spine and
hip fractures
• Are a major indication for pharmacotherapy
• Consider Vertebral Fracture Assessment
(VFA) if vertebral fracture is suspected
clinically
Xu WW, et al. Bone. 2011;2:307-311. National Osteoporosis Foundation. Clinician’s Guide
to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis
Foundation; 2013. Available at: http://www.nof.org/hcp/clinicians-guide . Accessed
September 13, 2013.
Identifying High-risk Patients in
Clinical Practice – Summary
• Primary goal: fracture prevention-therefore,
select patients based on risk of fracture
• Pharmacologic Therapy
– Patients with osteoporosis by DXA OR
– With a history of hip or spine fractures
• FRAX®
– Quantitative risk assessment
– Helps communicate risk to patients
– May increase treatment of high-risk patients and decrease
treatment of low-risk patients
Osteoporosis Management
• Nonpharmacologic
• Pharmacologic
Challenges With Current
Treatment Approaches
• Bone loss per se asymptomatic
• Patients may not appreciate fracture prevention
• No treatment agent meets the ideal profile—
inexpensive, easy to take, uniformly effective,
entirely free of risk
• Perceived risk of therapy may outweigh
perceived benefit
• Patient motivation to “adhere” and “persist” with
therapy may vary
Calcium Intake Recommendations
From the IOM
Estimated
Requirement (mg/day)
Recommended Dietary
Allowance (mg/day)
Upper Level Intake
(mg/day)
Infants 0 to 6 months
*
*
1,000
Infants 6 to 12 months
*
*
1,500
1–3 years old
500
700
2,500
4–8 years old
800
1,000
2,500
9–13 years old
1,100
1,300
3,000
14–18 years old
1,100
1,300
3,000
19–30 years old
800
1,000
2,500
31–50 years old
800
1,000
2,500
51–70 year-old male
800
1,000
2,000
51–70 year-old female
1,000
1,200
2,000
>70 years old
1,000
1,200
2,000
Life Stage Group
* For infants, adequate intake is 200 mg/day for 0 to 6 months of age and 260 mg/day for 6 to 12 months of age.
Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D: Report Brief. Washington, DC: IOM ; 2010.
Available at: http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx. Accessed
September 13, 2013.
Vitamin D Intake Recommendations
From the IOM
Estimated Avg
Requirement
(IU/day)
Recommended
Dietary Allowance
(IU/day)
Upper Level Intake
(IU/day)
Infants 0 to 6 months
*
*
1.000
Infants 6 to 12 months
*
*
1,500
1–3 years old
400
600
2,500
4–8 years old
400
600
3,000
9–13 years old
400
600
4,000
14–18 years old
400
600
4,000
19–30 years old
400
600
4,000
31–50 years old
400
600
4,000
51–70-year-old male
400
600
4,000
51–70-year-old female
400
600
4,000
>70 years old
400
600
4,000
Life Stage Group
* For infants, adequate intake is 400 IU/day for 0 to 6 months of age and 400 IU/day for 6 to 12 months of age.
Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D: Report Brief. Washington, DC: IOM; 2010.
Available at: http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx. Accessed
September 13, 2013.
Benefits of Exercise
What type?
– Weight-bearing
– Muscle-strengthening
Expected benefits?
–
–
–
–
Small (1% to 2%) effect on adult BMD
Reduces the loss of muscle mass
May reduce risk of falls by improving strength and balance
Regular walking decreases risk of hip fractures
Centers for Disease Control and Prevention. Injury Center. www.cdc.gov/injury.
Exercise – Some Caveats
– Patients may have nonskeletal factors that
increase the risk of falls and fractures
• Visual contrast sensitivity and depth perception1
• Women with wrist fractures—increased risk of future fractures1
– Forward flexion of spine and lifting can be
problematic2,3
• Low BMD in spine
• History of vertebral fractures
1. Edwards BJ, et al. Age Ageing. 2006;35:438-441. 2. Sinaki M. Pain Pract. 2013;13(1):68-75.
3. Myers ER, Wilson SE. Spine. 1997;22(24 Suppl):25S-31S.
Pharmacologic
Options
FDA-Approved Therapeutic Options
Prevention
Treatment
Estrogen
Calcitonin
Alendronate
Risedronate
Ibandronate
Zoledronic acid
Raloxifene
PTH (teriparatide)
Denosumab
Antiresorptive and Anabolic
Therapies
• Antiresorptive
• Decrease bone resorption
• Most treatment agents
• Examples: Bisphosphonates, SERMs, calcitonin,
estrogen, denosumab
• Anabolic
• Stimulate bone formation
• Example: teriparatide
Estrogen Treatment (ET)
• Several approved oral and transdermal preparations
• Treats symptoms of estrogen deficiency
• Skeletal effects:
– Decrease in biochemical markers of 50% to 60%
– 2-year BMD increase of 4% to 6% at hip and spine
– Decreased incidence of vertebral and hip fractures (34%) after 5
years in the Women’s Health Initiative (WHI)
– Effects in women with osteoporosis have not been evaluated in
randomized controlled trials
• Concern about adverse effects
• Long-term use not recommended
Rossouw JE, et al. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.
The Concept of a SERM
Selective Estrogen Receptor Modulator
(EAAs: Estrogen Agonist/Antagonists)
• Binds to the estrogen receptors
• Produces an estrogen agonist effect in some
tissues
• Produces an estrogen antagonist effect in
others
Raloxifene
• Raloxifene (60 mg daily)
• Skeletal effects:
– Decrease in biochemical markers of 30%
– 3-year BMD increases of 2% to 3% at hip and spine
– Decreased incidence of vertebral fractures (30% to 50%) in
women with pre-existing vertebral fractures or low bone density.
No effect on nonvertebral or hip fractures has been observed
• Extra-skeletal effects: reduction in invasive
breast cancer
Ettinger B, et al. JAMA. 1999;282:637-645.
Raloxifene
• Adverse effects
– Hot flashes
– 2- to 3-fold increased risk of venous
thromboembolic events
– No increased risk of stroke, but Black Box
Warning for increased risk of death following
stroke
– Leg cramps
Sontag A, Wan X, Krege JH. Curr Med Res Opin. 2010;26:71-76.
Calcitonin
• Calcitonin (200 units daily by nasal spray)
• Skeletal effects:
– Decrease in biochemical markers of 20%
– Small effect (1% to 2%) on bone density in spine
– Reduced incidence of vertebral fractures (36%) in women with preexisting vertebral fractures
– No effect on nonvertebral or hip fractures has been observed
• Adverse effects
– Nasal stuffiness
– Possible increased cancer risk
Chesnut CH 3d, et al. Am J Med. 2000;109:267-276.
http://effectivehealthcare.ahrq.gov/slides/?pageaction=displaySlides&tk=49&dpg=9&scroll=314. Accessed: September
13, 2013. European Medicines Agency. Press release. July 20, 2012. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/07/WC500130122.pdf. Accessed:
September 13, 2013.
Bisphosphonates
Alendronate, Risedronate, Ibandronate, and Zoledronic Acid
• Alendronate: 10 mg daily (tablet) or 70 mg weekly (tablet or
liquid) for treatment, 5 mg daily or 35 mg weekly for
prevention
• Risedronate: 5 mg daily or 35 mg weekly (tablet); 150 mg
monthly (tablet)
• Ibandronate: 150 mg monthly by tablet; 3 mg intravenously
over 15 to 30 seconds every 3 months
• Zoledronic acid: 5 mg by intravenous infusion over a
minimum of 15 minutes once every year for treatment—and
every other year for prevention
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National
*
Osteoporosis
Foundation; 2013. Available at: http://www.nof.org/hcp/clinicians-guide. Accessed September 13, 2013.
2012 Jun 25;172(12):930-6
Bisphosphonates: Indications
• Treatment and prevention of postmenopausal
osteoporosis
– Alendronate, risedronate, ibandronate, zoledronic acid
• Prevention and/or treatment of glucocorticoidinduced osteoporosis
– Risedronate, zoledronic acid, alendronate
• Treatment of men with low bone density
– Alendronate, risedronate, zoledronic acid
Bisphosphonates: Effects
Alendronate, Risedronate, Ibandronate and Zoledronic Acid
• Increased bone density in the spine by 5% to 8% and at
the hip by 3% to 6% after 3 years
• Reduced incidence of vertebral fractures by 40% to 70%
• Alendronate, risedronate and zoledronic acid reduced
non-vertebral fractures (25% to 40%), including hip
fractures (40% to 60%), in women with osteoporosis
• Ibandronate: Overall, no effect observed on non-vertebral
or hip fractures. In a post-hoc analysis, non-vertebral
fracture reduction was seen in a high-risk subgroup with
a baseline femoral neck T-score less than -3.0
Bisphosphonates
Contraindications/Warnings/Precautions
–
Hypocalcemia
–
Creatinine clearance <30 cc/min (<35 cc/min for zoledronic acid)
–
For oral dosing: Esophageal stricture or impaired esophageal motility (alendronate);
inability to stand or sit for at least 30 minutes (alendronate/risedronate) or 60
minutes (ibandronate)
Notes: UGI symptoms per se are not a contraindication to oral dosing.
Use in pregnancy: Class C
Oral dosing requirements
–
Tablets (with exception of delayed release risedronate) taken on an empty stomach
after overnight fast with 6 to 8 oz of plain water while in an upright position
–
Patients should not eat or lie down for at least 30 minutes (alendronate
and risedronate) or 60 minutes (ibandronate)
–
Calcium and vitamin D supplements, if needed, should be taken at a different time
of day than the oral bisphosphonate
National Osteoporosis Foundation. Med Lett. 2011;53(1360):24.
Bisphosphonates: Side Effects
• “Class warning” regarding UGI symptoms
(no increase in UGI complaints in randomized
controlled trials)
• Influenza-like symptoms may occur after first
monthly oral dose of IV bisphosphonate
• “Class warning” regarding infrequent bone,
joint, and/or muscle pain
• “Class warning” regarding jaw osteonecrosis
• “Class warning” about atypical fractures
following long-term therapy
“Osteonecrosis” of the Jaw (ONJ)
• An area of exposed alveolar or palatal bone that
typically shows poor healing over several months
– 95% of cases have been reported with high-dose,
chronic IV bisphosphonate treatment of myeloma and
cancer metastatic to bone1
– Can occur with denosumab2
– Pain in 2/3 cases: infection may or may not be present
– Known risk factors: invasive dental procedures, oral
trauma, periodontitis, poor oral hygiene, radiotherapy to
the jaw, chemotherapy, corticosteroids, infection
– Pathogenesis is not known3
1. Woo SB, et al. Ann Intern Med. 2006;144:753-761. 2. Sutton EE, Riche DM. Ann Pharmacother. 2012;46:1000-1009.
3. Khosla S, et al. J Bone Miner Res. 2007;22:1479-1491.
Atypical Fractures of Femur in Patients
Taking Anti-Resorptive Agents Long Term
• May begin with stress reaction or stress
fracture of lateral femoral cortex (A)
• Transverse fractures of femoral
diaphysis or in subtrochanteric region
(B)
• Often bilateral
• Prodromal pain in thigh or groin in 70%
• Occurs in untreated patients, but
increased incidence with long-term
antiresorptive therapy, particularly
bisphosphonates and denosumab
Park-Wyllie LY, et al. JAMA. 2011;305:783-789. Shane E, et al. J Bone Miner Res. 2013 May 28. [Epub ahead of print].
Watts NB, Diab DL. J Clin Endocrinol Metab. 2010;95:1555-1565. Meier RP. Arch Intern Med. 2012;172:930-936.
FDA Safety Update
• Be aware of the possibility of atypical fractures in
patients taking bisphosphonates
• Evaluate any patient who presents with new groin
or thigh pain to rule out fracture of the femoral
shaft
• Discontinue potent antiresorptive medication in
patients with atypical fractures
• Periodic reevaluation of need to continue
bisphosphonate therapy, particularly in patients
treated > 5 years
FDA. MedWatch Online Voluntary Reporting Form. https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm.
Accessed: September 13, 2013. Whitaker M, et al. N Engl J Med. 2012;366(22):2048-2051.
Bisphosphonate Therapy:
“Long-Term” Treatment
• Stopping treatment in high-risk patients
– After 5 years of alendronate-decline in BMD, rise in biochemical
markers, no increased fracture risk except clinical vertebral fractures1
– After 3 years of risedronate, spine BMD rose, vertebral facture risk
was still reduced compared with control patients2
– After 3 years of zoledronic acid, slight increase in morphometric
fractures vs clinical vertebral fractures3
• Long-term treatment has not clearly been associated with safety
issues or loss of efficacy
• Cessation of treatment after 2 to 5 years is associated with some
persisting effect on biochemical markers, as well as BMD; this has
been best characterized for alendronate and zoledronic acid
1. Black DM, et al. JAMA. 2006;296:2927-2938. 2. Watts NB, et al. Osteoporosis Int. 2008;19:365-372. 3. Black DM, et al.
J Bone Miner Res. 2012;27:243-254.
Bisphosphonate Holidays
• In patients at high risk for fractures, continued treatment
seems reasonable. Consider a drug holiday of 1 to 2 years
after 10 years of treatment
• For lower risk patients, consider a “drug holiday” after 4 to 5
years of stability
• Follow BMD and bone turnover markers during a drug
holiday period, and reinitiate therapy if bone density declines
or markers increase
Watts NB et al; AACE Osteoporosis Task Force. Endocr Pract. 2010;16(Suppl 3):1-37.
Whitaker M, et al. N Engl J Med. 2012;366(22):2048-2051.
Denosumab
• Monoclonal antibody to RANKL
• 60 mg subcutaneous injection every 6 months
• 9% increase in spinal BMD after 3 years in the pivotal
FREEDOM trial; 4% to 5% increase in hip BMD
• Reduction in fracture risk after 3 years:
– 68% decrease in new vertebral fractures
– 40% decrease in hip fractures
– 20% decrease in nonvertebral fractures
• 8-year data: continued increase BMD, reduced bone
turnover, good safety
Cummings SR, et al. N Engl J Med. 2009;368:756-765
Prolia (prescribing information). Thousand Oaks, CA: Amgen; June 2012.
McClung MR, et al. Osteoporos Int. 2013;24(1):227-235.
Denosumab Adverse Events
Adverse events that occurred more commonly in
denosumab group (as listed in the PI):
– Serious infections leading to hospitalization
– Dermatitis, eczema, rashes
– Back pain, pain in the extremity, musculoskeletal
pain, hypercholesterolemia, cystitis
– Pancreatitis
– Osteonecrosis of the jaw
– Significant suppression of bone remodeling
Prolia (prescribing information). Thousand Oaks, CA: Amgen; June 2012.
Teriparatide: rhPTH [1-34]
•
•
•
•
The only treatment agent that is anabolic—stimulates bone
formation rather than inhibiting bone resorption
20 μg daily (subcutaneously) for no more than 2 years
Indication: treatment of men and postmenopausal women
with osteoporosis who are at high risk for fracture
Effects:
– Increased bone density in spine by 9% and hip by
3% vs placebo over 18 months
– Reduced incidence of vertebral fractures (65%) and
nonvertebral fragility fractures (53%) in women with
pre-existing vertebral fractures
– Studies too small to evaluate effect on hip fractures
•
Adverse reactions: arthralgia, pain, nausea; warning about
osteosarcoma risk in rats
Neer RM, et al. N Engl J Med. 2001;344:1434-1441.
Forteo (prescribing information). Indianapolis, IN: Eli Lilly and Company; March 21, 2012.
BMD Doesn’t Fully Predict the
Reduction in Fracture Risk
• Antiresorptive treatment decreases fracture risk more
rapidly and to a larger extent than one would predict
from the relatively small changes in BMD1
– Fracture protection can be observed in the absence
of a significant change in BMD2
• Fracture protection persists even when the BMD
reaches a plateau
– BMD stability does not mean “nonresponse”
1.
2.
Harrington JT, et al. Calcif Tissue Int. 2004;74:129-135.
Wasnich RD, Miller PD. J Clin Endocrinol Metab. 2000;85:231-236.
Treatment: Summary
Safe and effective therapies are available
Antiresorptive agents
•
•
•
•
Prevent bone loss and preserve architecture
Improve quality of bone
Reduce the risk of vertebral fractures (all agents)
Alendronate, risedronate, zoledronic acid, and denosumab
proved to reduce the risk of nonvertebral and hip fractures
Anabolic agent: rhPTH [1-34] (teriparatide)
• Increases bone density and size
• Improves quality of bone
• Reduces the risk of vertebral and nonvertebral fractures;
no hip fracture data
Patient factors determine the most appropriate drug to use
Treatment Considerations
The right medication for the right patient
at the right time
• Susceptibility to side effects
– Past history of DVT – no estrogen or raloxifene
– Esophageal stricture – use of IV bisphosphonates
or denosumab
• Dosing/convenience
• Adherence
Sharon –
Updated Medical History
• This winter, Sharon slipped on wet leaves
and fell on the grass, fracturing her wrist
• How does the current fracture impact on clinical
decision-making?
• Should Sharon have an updated DXA?
• Should any laboratory tests be requested?
DXA at age 58
62
Evaluation of the Patient
With Osteoporosis
• 37% to 63% of patients with osteoporosis and/or
fractures have been found to have previously
unrecognized underlying disorders affecting bone
(eg, vitamin D deficiency, hypercalciuria, calcium malabsorption, hyperthyroidism,
multiple myeloma, etc)
• All patients need evaluation prior to initiation of
pharmacologic therapy:
– Careful history and examination
– Lab testing
o
o
o
o
o
Chemistry (Ca, P, Alk Phos, Cr, LFT’s)
CBC
24-hour urine calcium
25 OH vitamin D
TSH if taking thyroid hormone or symptoms
Sensitivity: 92%
Tannenbaum C, et al. J Clin Endocrinol Metab. 2002;87:4431-4437.
Sharon
• Sharon’s laboratory tests are normal
• She considers her individualized risk,
and chooses an antiresorptive agent
• Sharon does fairly well with her onceweekly agent for the first 3 months
• She fails to refill her prescription for several weeks
• Over the next several months, she often misses
her weekly dose
Adherence to Treatment in
Osteoporosis Patients
Percent Adherent on Weekly
Bisphosphonate
Most Patients Discontinue Oral
Bisphosphonates
Soon After Treatment Initiation
100
Rapid drop in persistence
due to nonacceptance
80
Further decrease in persistence due to
multiplicity of factors
60
40
20
0
0
3
6
9
12
Months Following Therapy Initiation
With permission from Springer Science+Business Media: Weycker D, et al. Compliance with drug therapy for
postmenopausal osteoporosis, Osteoporos Int, 2006;17:1645-1652. Figure 1. © International Osteoporosis
Foundation and National Osteoporosis Foundation 2006.
Adherence With
Osteoporosis Therapies
• Clinical trials
– Good adherence (usually >80%)
– Significant reduction in risk of vertebral,
nonvertebral, and hip fractures1
• Real-world adherence is poor
– Up to 83% of patients nonadherent with prescribed
osteoporosis Rx2-4
– Poor correlation was reported between patient and
physician perceptions of compliance
• Consequences of poor adherence
– Magnitude of risk reduction for hip and vertebral
fractures lower than expected4,5
1. Siris ES, et al. Am J Med. 2009;122(2 suppl):S3-S13. 2. Hamilton B, et al. Osteoporos Int. 2003;14:259-262.
3. Yood RA, et al. Osteoporos Int. 2003;14:965-968. 4. Caro JJ, et al. Osteoporos Int. 2004;15:1003-1008.
5. Eastell R, et al. Calcif Tissue Int. 2003;72:408. Abstract P-297.
Why Do Patients Resist Change?
Historically, several notions have been
proposed as to why patients struggle with
adherence to treatment plans:
– Denial or lack of insight
– Lack of knowledge
– Lack of skills
– Lack of caring
Butterworth SW. J Manag Care Pharm. 2008;14(6 Suppl S-b):S21-S25.
Improving Adherence
• Assess patient beliefs/understanding
• Understand current medication use
patterns
• Identify patients likely to be nonadherent
Impact of Lack of
Patient Education
In Canadian study of postmenopausal osteoporotic
patients said their doctors
• Did not always give them adequate information
about their medications
• Did not communicate this information in a format
that was easy to comprehend
Lack of communication with the HCP was perceived
to be a major factor affecting adherence
Lau E, et al. Can Fam Physician. 2008;54:394-402.
Side Effects and Adherence
• Discuss side effects of the medicines
• Put into perspective of risk vs benefits
• Reiterate patient's high risk of fracture
• Address other information sources
(media, Internet, friends)
– May deter from starting
– Encourage to stop use
Motivational Interviewing
• Open-ended
• Express empathy
• Roll with resistance
• Support autonomy
• Explore ambivalence
• Create an action plan
Butterworth SW. J Manag Care Pharm. 2008;14(6 suppl S6):S21-24.
Solomon DH, et al. Osteoporos Int. 2010;21:137-144.
Patient-Centered Medical Home
(PCMH): Osteoporosis Management
IMPROVED
OUTCOMES
Practice
Organization
•
Around osteo
management
Quality
Measures
•
Health IT
•
•
Pt reminders
Pt support, tx
Patient
Experience
Optimizing FX • Support
prevention
• Adherence
Family Medicine
Summary of Optimal
Osteoporosis Management
• Utilize tools to identify high-risk patients
• Target any patient with a fracture for evaluation
• Ensure adequate calcium and vitamin D
• Promote physical activity
• Discuss medicine options with high-risk patients
• Remove barriers to adherence
Introduction to
Osteoporosis PI
Activity
Questions