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Teriparatide in osteoporosis
• In 2013, sources estimate that 50 million people in
India are either osteoporotic or osteopenic
2
Indian Journal of Endocrinology and Metabolism / Jul-Aug 2014 / Vol 18 | Issue 4
Osteoporosis at the spine and hip was present in
 42.7% and 11.4% subjects using the Hologic database
and
 in 27.7% and 8.3% subjects using the ICMR database.
Low BMD, Inadequate Ca and Vitamin D and
Long term Glucocorticoid use
Consequences:
• the elevated morbidity and mortality of
fractured subjects
•increased socio-economic costs.
• Osteoporotic fractures, more than 75% of
which occur in women, are a major cause
of death, disability, and worldwide health-
care expenditure.
– Lancet 2015; 386: 1147–55
The International Osteoporosis
Foundation
• estimates that 1.6 million hip fractures occur annually worldwide; for the
year 2050, this figure is projected to reach 4.5 to 6.3 million
• Bone 67 (2014) 246–256
• Osteoporotic fractures are associated with chronic pain, disability, and an
increased risk of death, thus placing a significant burden on the health care
systems of countries worldwide.
Medicine 2015; 94(44):e1674
.
• In particular, hip fractures constitute the most serious of all osteoporotic
fractures; they are associated with increased morbidity and mortality, and
decreased ambulation, and are responsible for direct and indirect lifetime costs in
excess of $20 billion in the United States of America (estimated cost in 1997) and
over £12 billion in the United Kingdom (in 2012).
• By 2025, annual costs for osteoporosis-related fractures worldwide are projected
to increase by 50%
Mrs.Deshpande
• 62-year-old lady from Sangli town
• Educated
• 5′4″; 75Kgs
• 10 years postmenopause
• DXA performed 4 years ago
– Spine T-score: -2.1
– Right hip T-score (of neck): -1.6
Personal History
• Her mother suffered hip fracture in her 70s
• Performs weight-bearing exercise 3 times
per week
• Nonsmoker + never drinks alcohol
• Takes 1 calcium supplement each day –
unknown dose
• Consumes no dairy products and no
vitamin D
Worried because of
family history —consults you
What is the next step?
BMD Testing
Recommendations
• USPSTF/ NOF
– ALL women 65+
– MEN >/= 70
– Younger postmenopausal women and men 50-
70 with clinical RF’s
– Adults with fracture after age 50
– Adults with a condition or a medication a/w low
bone mass
– Perimenopausal women with high-risk risk
factors (ie-meds, low BMI, h/o low-trauma
fracture)
Screening Methods
• Dual-energy x-ray absorptiometry =
preferred
– Femoral neck BMD is best predictor of
hip fx
– Forearm BMD predicts non-hip fractures
• Ultrasound densitometry (sahara
screen)
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.
Strong Relationship Between
Bone Density and Bone Strength
• Bone density accounts for 60% to 80%
of bone strength in untreated patients1
• Best early predictor of fracture risk2
• Permits diagnosis before fractures
T-score
RelativeRisk
ofHipFracture
0
10
20
30
-5 -4 -3 -2 -1 0
1. Kushida K. Clin Calcium. 2004;14:11-17.
2. Fogelman J, Blake GM. J Nucl Med. 2000;41:2015-2025.
10-YearProbabilityof
SymptomaticFracture(%)
Age Is a Major Risk Factor
for Fracture
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.
80
70
60
50
AGE
Age 50
T-score -2.5
12% Fx Risk
Age 70
T-score -2.5
24% Fx Risk
-3 -2 -1
2010 Guidelines for Bone Density Testing
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.
• 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 COPD, RA, hyperparathyroidism, celiac disease, IBD
o Oral glucocorticoids, anticonvulsants, proton pump
inhibitors, SSRIs, aromatase inhibitors
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.
Male Osteoporosis
• Morbidity and mortality much higher in men than women with
osteoporotic fracture
• Secondary causes more common accounting for 50%
– ETOH (15-20%), glucocorticoid (20%), and hypogonadism (15-20%)
• Androgens may inhibit bone resorption
• 3-6% of men in US (NHANES III study)
– 28-47% with osteopenia
• 1/3 of men 60+ are likely to have an osteoporotic fracture
• Average onset is 10 yrs later than in women
• Men often asymptomatic at onset
Male Osteoporosis
• Previously, no formal recommendations
• Now, WHO recommends BMD for
– ALL men >70
– Men 50-70 with risk factors
• BMD should be compared to male
references so that osteoporosis diagnoses
are not missed
– BMD of hip is most reliable indicator due to
prevalence of spinal degenerative changes
10-year risk of fractures:
≥3% for hip fracture
or
≥20% for a major osteoporotic fracture
T-scores between
-1.0 and -2.5 and
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
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.
Teriparatide in osteoporosis
Teriparatide in osteoporosis
Answering Risk Factor
Questions in FRAX®
1. 1. National Osteoporosis Foundation. FRAX® Implementation Guide. Available at: http://www.iscd.org/wp-
content/uploads/2012/10/FRAXImplementationGuide_000.pdf . Accessed September 13, 2013.
2. 2. Kanis J, et al. Osteoporosis Int. 2005;16:581-589.
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
Select DXA manufacturer and enter BMD (g/cm2)
Use Femoral Neck Bone
Mineral Density (BMD) only
FRAX® Caveats:
Entering Bone Density Data
NOF Guidelines:
≥20% major fx
≥3% hip fx
Mrs.Deshpande- After DEXA
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
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.
“Specific treatment decisions must be individualized”
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.
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
• Patient motivation to “adhere” and “persist”
with therapy may vary
Osteoporosis a Nightmare of Post menopause/ old age
Osteoporosis
31
DEFINITION
Systemic, skeletal disease characterized by
low bone mass &
Structural deterioration of bone tissue
Leading to bone fragility &
Increased susceptibility to fracture.
Silent until a fracture occurs !
Microarchitecture changes in
osteoporosis
Bone mass
Trabecular
thickness
Trabecular number
Connectivity
32
OSTEOPOROSIS
• A major health problem
• Inadequate Ca intake
• Increasing longevity
• Postmenopausal state
• Morbidity: FRACTURES
• Mortality
• Osteopenia is common
in healthy Indians as
well
The auntyji next door
Normal bone
Osteoporotic bone
Osteomalacic bone
MALACIA vs POROSIS
• MALACIA
• Anatomic bone
volume unchanged
• Volume of specific
bone tissue
unchanged
• Less mineral content
• Increased organic
matter
• POROSIS
• Bone size unchanged
• Cortical and
trabecular thinning
• Bone tissue reduced,
fat tissue increased
• Ratio of mineral to
organic matter
unchanged
Cement mein rait
OSTEOMALACIA VS. POROSIS
• MALACIA
• Defective
mineralization
• Vit D deficiency
predominates
• Proximal myopathy
• Painful bones
• Low Ca, high ALP
• Check renal status
• POROSIS
• Defective bone
formation
• Ca def predominates
• Asymptomatic until
fracture occurs
• Back pain
(paraspinal)
• Loss of height
• Low Ca, P, ALP
OSTEOMALACIA VS. POROSIS
• MALACIA
• Evenly distributed
abnormalities of vertebral
shape
• Lumbar spine
• Superior and inferior
margins equally affected
in biconcave deformity;
smooth appearance
• POROSIS
• One or more
abnormal vertebrae;
separated by several
normal ones
• Thoracic spine
• Irregular involvement
of endplates
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.
TREATMENT OF
OSTEOPOROSIS
41
Non-pharmacologic approaches
• Maintaining adequate intake of calcium [1000-1300
mg/day], vitamin D [800-2000 IU], and protein;
• Exercise: Performing adequate weight-bearing
physical activity and exercise to maintain or improve
balance and posture;
• Limiting the risk of falls
• lifestyle changes, such as smoking cessation and
moderating alcohol intake.
42
To keep bone healthy
43
Exercise
regularly
Educate proper lifting
techniques
44
Avoid falls
45
Calcium and Vitamin D
46
Maintaining adequate intake of calcium [1000-
1300 mg/day], vitamin D [800-2000 IU], and
protein;
Calcium, Vitamin D and its Analogs supplements are recommended for all patients
Therapeutic Choices
MAINTAIN BONE BUILD BONE
ANTIRESORPTIVE THERAPY ANABOLIC THERAPY
Targets Osteoclasts Targets Osteoblasts
Reduces bone turnover Increases bone formation
Reduces cortical porosity Increases trabecular bone volume
Increases BMD Increases BMD
Reduces fracture risk Improves cancellous microarchitecture
Increases cortical thickness
Reduces fracture risk
e.g. Bisphosphonates, SERMs,
calcitonin, estrogen, denosumab
e.g. Teriparatide
SERMs: 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
48
Raloxifene 60 mg daily
• Adverse effects
– Hot flashes
– 2- to 3-fold increased risk of venous thromboembolic events
– Increased risk of death following stroke
– Leg cramps
Sontag A, Wan X, Krege JH. Curr Med Res Opin. 2010;26:71-76.
• Skeletal effects:
– 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.
Calcitonin
• Calcitonin (200 units daily by nasal spray)
• Skeletal effects:
– Small effect (1% to 2%) on bone density in spine
– Reduced incidence of vertebral fractures (36%) in women with pre-
existing 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.
Bisphosphonates: Effects
• 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.
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.
Choice of drug
• Is determined based on evidence for effectiveness of each drug and
in accordance with the age, fracture risk, and pathophysiology of
each patient.
Clin Calcium. 2015 Sep;25(9):1285-92. doi: CliCa150912851292.
• Unlike most chronic diseases, osteoporosis treatments are generally
limited to a single drug at a fixed dose and frequency.
• Nonetheless, no approved therapy is able to restore skeletal
integrity in most osteoporotic patients and long-term use of
osteoporosis drugs is controversial.
• Thus, many patients are treated with the sequential use of two
or more therapies
Lancet. 2015 Sep 19;386(9999):1147-55.
55
Limitations of currently available
drugs
56
Limitations of currently available
drugs
• Use of Bisphosphonates, particularly for long periods of
time (5-7 years), is associated with an increased risk of
atypical femoral fracture (AFF)
J Bone Metab 2015;22:183-189
• Osteonecrosis of Jaw (ONJ) is a rare complication, that
may occur in patients receiving high dose intravenous
bisphosphonate or denosumab therapy
• Data from Post-marketing surveillance and experimental
studies found a 0.7-2.4% increase in rate of cancer with
long term use of calcitonin
• Risk of venous thromboembolism and stroke with
raloxifene
• Despite fracture risk reduction with antiresorptives,
FRACTURE MAY STILL OCCUR
J Obstet Gynaecol Can 2014;36(9 eSuppl C):S1–S15
Clinical Need for Teriparatide in
Osteoporosis
• While current treatments [BsP, SERMs, HRT
and Calcitonin] reduce fracture risk and
allay bone loss, many patients remain
at significant fracture risk
• Current treatments are unable to
restore bone matrix or architecture
Teriparatide
In
Osteoporosis
Teriparatide
Drug Profile
61
Teriparatide Injection [rhPTH(1-34)]
• First [only available at present] clinically
useful bone formation agent
• activates osteoblasts and stimulates formation of
new bone
• increases bone mass (greatest increase in BMD observed at the
lumbar spine) and restores skeletal architecture
62
Control Teriparatide
Effect Of Teriparatide On Skeletal Architecture
Baseline
Follow up: 21 Months Treatment
Jiang et al., J Bone Miner Res 2003;18:1932-40
Eriksen, Drugs Today 2004;40:935-948
Patient treated with
teriparatide 20µg
Female, age 65
Duration of therapy: 637 days (approx. 21 months)
BMD Change:
Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%)
Total Hip: +5.2% (group mean = 2.6 ± 4.9%) 6
3
FOR/CYCLE2/2016/02427S1
USFDA Approved Indication
since 2002
For the treatment of Severe Osteoporosis including
1. Treatment of Postmenopausal Women with
Osteoporosis at High Risk for Fracture
2. Increase of Bone Mass in Men with Primary or
Hypogonadal Osteoporosis at High Risk for
Fracture
3. Treatment of Men and Women with Glucocorticoid-
Induced Osteoporosis at High Risk for Fracture
DCGI approved indication and Forteo PI March 2012
Teriparatide Injection [rhPTH(1-34)]
• 20 µg daily subcutaneous administration.
• Should not be given for more than 2 years- WHO
Hepatic Impairment
No studies have been performed in patients with hepatic impairment.
Renal Impairment
In 5 patients with severe renal impairment (CrCl<30 mL/min), the AUC and T1/2 of
teriparatide were increased by 73% and 77%, respectively. Maximum serum
concentration of teriparatide was not increased
Check Ser Calcium and Ser PTH Level before starting
Urolithiasis or Pre-existing Hypercalciuria
If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of
urinary calcium excretion should be considered. Teriparatide should be used with
caution in patients with active or recent urolithiasis because of the potential to
exacerbate this condition.
Teriparatide
Evidence
66
Teriparatide
Compared to placebo and Bsp
[Alendronate]
67
Fracture Prevention Trial [FPT]:
Pivotal Trial in Women
• Prospective, randomized, double-blind trial
performed at 99 sites in 17 countries
• 1637 postmenopausal women with a prevalent
vertebral fracture
• Primary endpoint: Proportion of women with
one or more new vertebral fractures
• Teriparatide 20 µg, 40 µg, or placebo by once
daily self-injection
N Engl J Med 2001;344:1434-41.
FPT: Fracture Incidence in Postmenopausal
Women
69
Teriparatide
d p≤0.025 compared with placebo
FPT: Treatment with teriparatide
• Reduced the risk of vertebral fractures by 65%
• Reduced the risk of new multiple vertebral
fractures by 77%
• Reduced the risk of nonvertebral fragility fractures
by 53%
• Increased BMD at the spine and hip
• Improved bone microarchitecture
70
FACT: Forteo Alendronate Comparator Trial
• 203 postmenopausal women with osteoporosis in an
18-month randomized parallel double-blind study
compared Teriparatide vs. alendronate [10 mg] on
BMD and markers of bone turnover.
Arch Intern Med. 2005 Aug 8-22;165(15):1762-8.
TPTD ALN
At 6 months
markers of bone turnover
increased Decrease P<.001
At 18 months, areal spine BMDs 10.3% 5.5% [P<.001
]
At 18 months, volumetric spine
BMDs
19 % 3.8 % [P<.01]
Areal femoral neck BMD 3.9% 3.5%
Increases in BMD by opposite mechanisms of action on bone
remodeling.
Teriparatide
After Antiresorptive
EUROFORS: European Forsteo
Study
• A 2-yr, prospective, controlled, randomized, open-label
clinical trial of 868 postmenopausal women with
established osteoporosis.
• Study consisted of two substudies (1 and 2) and two
treatment phases and was conducted at 95 centers
in 10 European countries.
• Patients were classified into three groups
(1) treatment-naïve
(2) pretreated with antiresorptive drugs (AR pretreated), and
(3) AR pretreated with inadequate clinical
outcome (inadequate AR responders).
J Bone Miner Res 2008;23:1591–1600.
EUROFORS: European Forsteo Study
J Bone Miner Res 2009;24:726–736.
EUROFORS: Substudy 1
• At 12 moths, all treatment- naı¨ve and AR pretreated
participants were randomized (3:1:1) to
 Continue teriparatide (treatment arm 1) [n=305],
 Switch to raloxifene 60 mg/d (treatment arm 2) [n=100], or
 Receive no active treatment (treatment arm 3) [n=102], for the
second year
75
EUROFORS Substudy 1 Results
76
EUROFORS: Substudy 1
conclusion
1) A second year of teriparatide is associated with significant
progressive BMD increases at both the lumbar spine and hip,
2) Sequential therapy with raloxifene after 1 yr of teriparatide
maintains the BMD gains at the lumbar spine and further increases
BMD at the hip, and
3) Sequential therapy with Ca and Vit D alone is associated with a
partial loss of the spine BMD that was previously gained with
teriparatide.
 Findings indicate that raloxifene would be a suitable sequential
treatment after teriparatide. Raloxifene may be of particular value in
patients who use teriparatide because of an inability to tolerate
bisphosphonates.
EUROFORS: Effects of Two yrs daily
TPTD Patients from Substudy 1 & 2
Examined BMD response and safety in a subgroup of 503
postmenopausal women with osteoporosis who received
teriparatide for 24 mo.
Treatment with teriparatide for 24 mo is associated with
 Significant increases in BMD at the lumbar spine, total hip, and femoral
neck, in patients with and without prior AR treatment. Prior AR
treatment modestly blunted the BMD response to teriparatide.
 24 months of daily teriparatide treatment results in significantly greater
increases in BMD compared with an 18-mo treatment period and with a
patient safety profile consistent with 18 months
J Bone Miner Res 2008;23:1591–1600.
79
FOR/CYCLE2/2016/02427S1
Teriparatide
Used as Switch or Add ?
80
Teriparatide: Switch or Add ???
81
In patients
previously treated
with antiresorptive
drugs
Switch
Stop the antiresorptive
agent when teriparatide is
initiated
Add
continue the antiresorptive
agent when teriparatide is
initiated
J Bone Miner Res. 2013 Jun;28(6):1328-
36. doi: 10.1002/jbmr.1853
Hip and spine strength effects of adding versus switching to
teriparatide in postmenopausal women with osteoporosis treated
with prior alendronate or raloxifene
• Many postmenopausal women treated with
teriparatide for osteoporosis have previously
received antiresorptive therapy
• In women treated with alendronate (ALN) or
raloxifene (RLX), adding versus switching to
teriparatide produce different responses
• Postmenopausal women with osteoporosis receiving
ALN 70 mg/week (n = 91) or RLX 60 mg/day
(n = 77) for ≥18 months were randomly assigned
to add or switch to teriparatide 20 µg/day.
82
J Bone Miner Res. 2013 Jun;28(6):1328-
36. doi: 10.1002/jbmr.1853.
Study scheme: Add or switch
83
J Bone Miner Res. 2013 Jun;28(6):1328-36. doi:
10.1002/jbmr.1853.
Effects of adding versus switching to teriparatide in
postmenopausal women with osteoporosis pretreated with
raloxifene or alendronate
84
J Bone Miner Res. 2013 Jun;28(6):1328-36. doi:
10.1002/jbmr.1853.
For the spine: in patients previously treated
with ALN or RLX, there were no differences
in the observed increases in either integral
vBMD or strength between the Add and
Switch groups.
For the RLX stratum, in the analysis of the
hip, adding teriparatide to RLX resulted in
an earlier increase in hip strength, but by 18
months there was no significant difference
in the improvement in integral hip vBMD or
strength in those who continued versus those
who stopped RLX.
In contrast, in the ALN stratum, hip vBMD
increased from baseline at both 6 and 18
months only in the Add group and hip
strength increased only in the Add group.
Hip and spine strength effects of adding versus switching to
teriparatide in postmenopausal women with osteoporosis treated
with prior alendronate or raloxifene
• Adding or switching to teriparatide conferred
similar benefits on spine strength in
postmenopausal women with osteoporosis
pretreated with ALN or RLX.
• Increases in hip strength were more variable.
– In RLX-treated women, strength increased more
quickly in the Add group; in ALN-treated women, a
significant increase in strength compared with
baseline was seen only in the Add group.
85
J Bone Miner Res. 2013 Jun;28(6):1328-
36. doi: 10.1002/jbmr.1853.
Teriparatide: Switch or Add ???
86
In patients
previously
treated with
antiresorpti
ve drugs
ALN/RLX
Switch
J Bone Miner Res. 2013 Jun;28(6):1328-
36. doi: 10.1002/jbmr.1853
Add
At risk of spine fracture
Add or switch with
Teriparatide
Similar outcome
At risk of Hip fracture
ALN pretreated: Add
Teriparatide with ALN
Better outcome
RLX pretreated: Add or
switch with Teriparatide
similar outcome
Teriparatide
Literature review: Teriparatide 20
μg/day at Hip
87
• Teriparatide increases bone formation throughout the
skeleton, including the hip and also increases hip
strength
• In clinical fracture-outcome trials, treatment with
teriparatide has been shown to reduce the risk of
nonvertebral fracture, a composite endpoint that includes
hip fracture.
• Body of evidence suggests that teriparatide positively
affects the hip in patients with osteoporosis.
A full 2-year course of Teriparatide
treatment
important to maximally increase hip BMD
Similar to EUROFORS, another two studies found
1. Patients switched from alendronate to teriparatide, Total hip
BMD decreased at 6 months (by 1.8%). With continued
teriparatide treatment, total hip BMD increased by
approximately 1.5% between months 6 and 18
2. Decrease in femoral neck BMD at 6 months followed by
2.6% increase after 12 moths with teriparatide
• data indicate that patients treated with antiresorptive therapy
and switched to teriparatide may experience a modest
decrease in hip BMD followed by a later increase in hip BMD;
for these patients, a full 2-year course of treatment with
teriparatide may be important to maximally increase hip BMD.
Teriparatide
In combination
90
Combination [TPTD + antiresorptive]
• Combining antiresorptive agents with PTH
or TPTD is a superior hip BMD outcome
compared with TPTD/PTH alone.
• Most evident when TPTD/PTH is
combined with a bisphosphonate or
denosumab.
91
Combination [TPTD + antiresorptive]
• In contrast to findings in the hip, in the
majority of studies, there is no benefit to
spine BMD with combination therapy vs
monotherapy.
92
Teriparatide
In Men
93
Teriparatide in Men: Pivotal Trial
• ORWOLL ES et al., 2003: Prospective
randomized trial performed at 34 sites in 11
countries
• 437 men with idiopathic or hypogonadal
osteoporosis (spine or hip T-score < -2 SD)
• Primary endpoint: Change in spine BMD
• Teriparatide 20 µg/day, 40 µg/day, or placebo by
once-daily self-injection
94
J Bone Miner Res 2003;18:9–17
Results: % change in BMD in lumbar
spine
95
Teriparatide results in an
increase in BMD and is a
potentially useful therapy for
osteoporosis in men
J Bone Miner Res 2003;18:9–17
Teriparatide Clinical evidence
Glucocorticoid Induced
Osteoporosis (GIO)
96
Teriparatide in Glucocorticoid Induced
Osteoporosis
• Teriparatide vs. Alendronate
– Increases in BMD with teriparatide at 18 months
were 2-fold higher than those associated with
alendronate (mean change from baseline 8.0%
compared with 3.9%; p < 0.001) [Drugs 2008]
– Similar increases in BMD from baseline were seen in
the teriparatide group than in the alendronate group
at 36 months; 11.0% versus 5.3% for lumbar spine,
5.2% versus 2.7% for total hip, and 6.3% versus 3.4%
for femoral neck (P < 0.001 for all). [Arthritis Rheum. 2009
Nov;60(11):3346-55. doi: 10.1002/art.24879.]
97
Teriparatide in fracture healing
Growing evidence yet unapproved at
present
98
Teriparatide in osteoporotic fracture
• Growing body of evidence suggest a role for Teriparatide in
the management of fractures.
– Studies in both normal and delayed healing models have shown
improvement in callus volume and mineralisation, bone mineral
content, rate of successful union and strength at fracture sites.
World J Orthop 2015 July 18; 6(6): 457-461
• Animal studies show teriparatide’s role in the enhancement of
fracture healing:
– Administration of teriparatide seems to have a positive influence
on callus formation and mechanical strength of tibial fractures in
rats
Injury, Int. J. Care Injured 47 S1 (2016) S36–S38
99
Teriparatide and bone healing
• Aspenberg et al.: compared teriparatide 20µg
versus placebo on time to radiographic healing of
distal radial fractures in postmenopausal women.
– Radiographic evidence of complete cortical bridging in 3 of
4 cortices happened earlier for patients assigned to
teriparatide (7.4 weeks) vs. placebo (9.1 weeks).
• Numerous case series state safety & potential
benefits of teriparatide use in patients recovering
from fractures.
– A cohort of 145 patients who had failed previous fracture
healing* 93% of patients demonstrated radiographic and
clinical union of their fractures with teriparatide 20µg
100
* Some form of nonunion or delayed union, or were high-risk candidates for healing acute
fracture
Teriparatide in fracture healing
• Research suggests Teriparatide may improve callus volume, callus
mineralisation, bone mineral content and successful union
• Significant improvements in rate of successful union at the fracture
site in both normal and delayed healing models has been
demonstrated
• Currently many United States physicians use Teriparatide “off
license” for fractures and non-unions
• We suggest more, well designed, human randomised controlled
trials are required before Teriparatide can become a mainstream
option in the management of fractures and non-unions.
• Teriparatide Improves Fracture Healing and
Early Functional Recovery in Treatment of
Osteoporotic Intertrochanteric Fractures
Tsan-Wen Huang, MD, Po-Yao Chuang, MD, Shih-Jie Lin, MD, Chien-
Yin Lee, MD, Kuo-Chin Huang, MD, Hsin-Nung Shih, MD, Mel S.
Lee, MD, PhD, Robert Wen-Wei Hsu, MD, and Wun-Jer Shen, MD
• Medicine (Baltimore). 2016 May; 95(19):
Radiographic features of teriparatide-induced healing
of femoral fractures
Youngwoo Kim ⁎, Chiaki Tanaka, Hiroshi Tada, Hiroshi Kanoe, Takaaki
Shirai Department of Orthopaedics, Kyoto City Hospital, 1-2 Mibu,
higashitakada-cho,
Nakagyo, Kyoto, Japan
Teriparatide in osteoporosis
• Teriparatide for acceleration of fracture
repair in humans: a prospective,
randomized, double-blind study of 102
postmenopausal women with distal radial
fractures.
• Aspenberg P, Genant HK, Johansson T, Nino AJ, See K, Krohn K,
García-Hernández PA, Recknor CP, Einhorn TA, Dalsky GP, Mitlak
BH, Fierlinger A, Lakshmanan MC
• J Bone Miner Res. 2010 Feb; 25(2):404-14.
• Parathyroid hormone 1-84 accelerates
fracture-healing in pubic bones of elderly
osteoporotic women.
Peichl P, Holzer LA, Maier R, Holzer G
• J Bone Joint Surg Am. 2011 Sep 7;
93(17):1583-7.
• Review Article
• Orthopedic uses of teriparatide.
• Bukata SV, Puzas JE
• Curr Osteoporos Rep. 2010 Mar; 8(1):28-33.
• Showed the beneficial effect of teriparatide
in delayed union of fractures.
• Average time to resolution of symptoms
and radiological healing was improved
• Successful treatment of sternal fracture
nonunion with teriparatide.
• Chintamaneni S, Finzel K, Gruber BL
• Osteoporos Int. 2010 Jun; 21(6):1059-63
• Teriparatide may accelerate healing in
delayed unions of type III odontoid
fractures: a report of 3 cases.
Rubery PT, Bukata SV
• J Spinal Disord Tech. 2010 Apr; 23(2):151-5.
My own experience
Day of injury
30 days later
Mrs.Parasnis 68 years old
30 days after starting teriparatide
Mr.Broachwala- 66 yearsOld
Teriparatide in osteoporosis
Teriparatide in osteoporosis
Teriparatide in osteoporosis
Teriparatide in osteoporosis
Teriparatide in osteoporosis
Teriparatide in osteoporosis
Additional Uses
• Teriparatide improves bone quality and
healing of atypical femoral fractures
associated with bisphosphonate therapy
• Cherie Ying Chiang; Roger M.D. Zebaze; Ali Ghasem-Zadeh; Sandra
Iuliano-Burns; Andrew Hardidge; Ego Seeman
• Bone; Volume 52, Issue 1, January 2013, Pages 360-365
Teriparatide in osteoporosis
Teriparatide in osteoporosis
Side effects of teriparatide
•Dizziness or tachycardia due to hypotension may rarely happen to
some patients within 4 hours after using this medication. These
symptoms may persist for a few minutes to a few hours. This side
effect goes away after several doses as the body adjusts to
teriparatide.
•pain, redness, bruising, itching, or swelling where the medicine
was injected;
•leg cramps;
•joint pain;
•cough, sore throat, runny nose;
•headache or neck pain;
•nausea, constipation, diarrhea.
Contra indications
• Avoid teriparatide use in patients with
• an increased baseline risk of osteosarcoma,
• those with Paget's disease,
• prior radiation therapy (external or seed implants),
• unexplained elevations of alkaline phosphatase, or
• in young adults with open epiphyses
• Metastatic bone disease
• Multiple myeloma
• Hypercalcemic states
• Breast feeding or pregnant mothers
CONCLUSIONS
• TREAT AGGRESSIVELY
• REDUCE FRACTURE RISK
• Anabolic therapy + Vit D + calcium
• Follow up with anti-resorptive therapy
• BE PRO-ACTIVE to IMPROVE BONE HEALTH
Teriparatide in osteoporosis

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Teriparatide in osteoporosis

  • 2. • In 2013, sources estimate that 50 million people in India are either osteoporotic or osteopenic 2 Indian Journal of Endocrinology and Metabolism / Jul-Aug 2014 / Vol 18 | Issue 4 Osteoporosis at the spine and hip was present in  42.7% and 11.4% subjects using the Hologic database and  in 27.7% and 8.3% subjects using the ICMR database. Low BMD, Inadequate Ca and Vitamin D and Long term Glucocorticoid use
  • 3. Consequences: • the elevated morbidity and mortality of fractured subjects •increased socio-economic costs. • Osteoporotic fractures, more than 75% of which occur in women, are a major cause of death, disability, and worldwide health- care expenditure. – Lancet 2015; 386: 1147–55
  • 4. The International Osteoporosis Foundation • estimates that 1.6 million hip fractures occur annually worldwide; for the year 2050, this figure is projected to reach 4.5 to 6.3 million • Bone 67 (2014) 246–256 • Osteoporotic fractures are associated with chronic pain, disability, and an increased risk of death, thus placing a significant burden on the health care systems of countries worldwide. Medicine 2015; 94(44):e1674 . • In particular, hip fractures constitute the most serious of all osteoporotic fractures; they are associated with increased morbidity and mortality, and decreased ambulation, and are responsible for direct and indirect lifetime costs in excess of $20 billion in the United States of America (estimated cost in 1997) and over £12 billion in the United Kingdom (in 2012). • By 2025, annual costs for osteoporosis-related fractures worldwide are projected to increase by 50%
  • 5. Mrs.Deshpande • 62-year-old lady from Sangli town • Educated • 5′4″; 75Kgs • 10 years postmenopause • DXA performed 4 years ago – Spine T-score: -2.1 – Right hip T-score (of neck): -1.6
  • 6. Personal History • Her mother suffered hip fracture in her 70s • Performs weight-bearing exercise 3 times per week • Nonsmoker + never drinks alcohol • Takes 1 calcium supplement each day – unknown dose • Consumes no dairy products and no vitamin D
  • 7. Worried because of family history —consults you What is the next step?
  • 8. BMD Testing Recommendations • USPSTF/ NOF – ALL women 65+ – MEN >/= 70 – Younger postmenopausal women and men 50- 70 with clinical RF’s – Adults with fracture after age 50 – Adults with a condition or a medication a/w low bone mass – Perimenopausal women with high-risk risk factors (ie-meds, low BMI, h/o low-trauma fracture)
  • 9. Screening Methods • Dual-energy x-ray absorptiometry = preferred – Femoral neck BMD is best predictor of hip fx – Forearm BMD predicts non-hip fractures • Ultrasound densitometry (sahara screen)
  • 10. 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
  • 11. 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.
  • 12. Strong Relationship Between Bone Density and Bone Strength • Bone density accounts for 60% to 80% of bone strength in untreated patients1 • Best early predictor of fracture risk2 • Permits diagnosis before fractures T-score RelativeRisk ofHipFracture 0 10 20 30 -5 -4 -3 -2 -1 0 1. Kushida K. Clin Calcium. 2004;14:11-17. 2. Fogelman J, Blake GM. J Nucl Med. 2000;41:2015-2025.
  • 13. 10-YearProbabilityof SymptomaticFracture(%) Age Is a Major Risk Factor for Fracture 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. 80 70 60 50 AGE Age 50 T-score -2.5 12% Fx Risk Age 70 T-score -2.5 24% Fx Risk -3 -2 -1
  • 14. 2010 Guidelines for Bone Density Testing 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. • 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 COPD, RA, hyperparathyroidism, celiac disease, IBD o Oral glucocorticoids, anticonvulsants, proton pump inhibitors, SSRIs, aromatase inhibitors
  • 15. 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.
  • 16. Male Osteoporosis • Morbidity and mortality much higher in men than women with osteoporotic fracture • Secondary causes more common accounting for 50% – ETOH (15-20%), glucocorticoid (20%), and hypogonadism (15-20%) • Androgens may inhibit bone resorption • 3-6% of men in US (NHANES III study) – 28-47% with osteopenia • 1/3 of men 60+ are likely to have an osteoporotic fracture • Average onset is 10 yrs later than in women • Men often asymptomatic at onset
  • 17. Male Osteoporosis • Previously, no formal recommendations • Now, WHO recommends BMD for – ALL men >70 – Men 50-70 with risk factors • BMD should be compared to male references so that osteoporosis diagnoses are not missed – BMD of hip is most reliable indicator due to prevalence of spinal degenerative changes
  • 18. 10-year risk of fractures: ≥3% for hip fracture or ≥20% for a major osteoporotic fracture T-scores between -1.0 and -2.5 and 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 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.
  • 19. 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.
  • 22. Answering Risk Factor Questions in FRAX® 1. 1. National Osteoporosis Foundation. FRAX® Implementation Guide. Available at: http://www.iscd.org/wp- content/uploads/2012/10/FRAXImplementationGuide_000.pdf . Accessed September 13, 2013. 2. 2. Kanis J, et al. Osteoporosis Int. 2005;16:581-589. 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
  • 23. Select DXA manufacturer and enter BMD (g/cm2) Use Femoral Neck Bone Mineral Density (BMD) only FRAX® Caveats: Entering Bone Density Data
  • 24. NOF Guidelines: ≥20% major fx ≥3% hip fx Mrs.Deshpande- After DEXA
  • 25. 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 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. “Specific treatment decisions must be individualized”
  • 26. 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.
  • 27. 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
  • 29. 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 • Patient motivation to “adhere” and “persist” with therapy may vary
  • 30. Osteoporosis a Nightmare of Post menopause/ old age
  • 31. Osteoporosis 31 DEFINITION Systemic, skeletal disease characterized by low bone mass & Structural deterioration of bone tissue Leading to bone fragility & Increased susceptibility to fracture. Silent until a fracture occurs !
  • 32. Microarchitecture changes in osteoporosis Bone mass Trabecular thickness Trabecular number Connectivity 32
  • 33. OSTEOPOROSIS • A major health problem • Inadequate Ca intake • Increasing longevity • Postmenopausal state • Morbidity: FRACTURES • Mortality • Osteopenia is common in healthy Indians as well The auntyji next door
  • 37. MALACIA vs POROSIS • MALACIA • Anatomic bone volume unchanged • Volume of specific bone tissue unchanged • Less mineral content • Increased organic matter • POROSIS • Bone size unchanged • Cortical and trabecular thinning • Bone tissue reduced, fat tissue increased • Ratio of mineral to organic matter unchanged Cement mein rait
  • 38. OSTEOMALACIA VS. POROSIS • MALACIA • Defective mineralization • Vit D deficiency predominates • Proximal myopathy • Painful bones • Low Ca, high ALP • Check renal status • POROSIS • Defective bone formation • Ca def predominates • Asymptomatic until fracture occurs • Back pain (paraspinal) • Loss of height • Low Ca, P, ALP
  • 39. OSTEOMALACIA VS. POROSIS • MALACIA • Evenly distributed abnormalities of vertebral shape • Lumbar spine • Superior and inferior margins equally affected in biconcave deformity; smooth appearance • POROSIS • One or more abnormal vertebrae; separated by several normal ones • Thoracic spine • Irregular involvement of endplates
  • 40. 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.
  • 42. Non-pharmacologic approaches • Maintaining adequate intake of calcium [1000-1300 mg/day], vitamin D [800-2000 IU], and protein; • Exercise: Performing adequate weight-bearing physical activity and exercise to maintain or improve balance and posture; • Limiting the risk of falls • lifestyle changes, such as smoking cessation and moderating alcohol intake. 42
  • 43. To keep bone healthy 43 Exercise regularly
  • 46. Calcium and Vitamin D 46 Maintaining adequate intake of calcium [1000- 1300 mg/day], vitamin D [800-2000 IU], and protein; Calcium, Vitamin D and its Analogs supplements are recommended for all patients
  • 47. Therapeutic Choices MAINTAIN BONE BUILD BONE ANTIRESORPTIVE THERAPY ANABOLIC THERAPY Targets Osteoclasts Targets Osteoblasts Reduces bone turnover Increases bone formation Reduces cortical porosity Increases trabecular bone volume Increases BMD Increases BMD Reduces fracture risk Improves cancellous microarchitecture Increases cortical thickness Reduces fracture risk e.g. Bisphosphonates, SERMs, calcitonin, estrogen, denosumab e.g. Teriparatide
  • 48. SERMs: 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 48
  • 49. Raloxifene 60 mg daily • Adverse effects – Hot flashes – 2- to 3-fold increased risk of venous thromboembolic events – Increased risk of death following stroke – Leg cramps Sontag A, Wan X, Krege JH. Curr Med Res Opin. 2010;26:71-76. • Skeletal effects: – 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.
  • 50. Calcitonin • Calcitonin (200 units daily by nasal spray) • Skeletal effects: – Small effect (1% to 2%) on bone density in spine – Reduced incidence of vertebral fractures (36%) in women with pre- existing 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.
  • 51. 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.
  • 52. Bisphosphonates: Effects • 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.
  • 53. 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.
  • 54. 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.
  • 55. Choice of drug • Is determined based on evidence for effectiveness of each drug and in accordance with the age, fracture risk, and pathophysiology of each patient. Clin Calcium. 2015 Sep;25(9):1285-92. doi: CliCa150912851292. • Unlike most chronic diseases, osteoporosis treatments are generally limited to a single drug at a fixed dose and frequency. • Nonetheless, no approved therapy is able to restore skeletal integrity in most osteoporotic patients and long-term use of osteoporosis drugs is controversial. • Thus, many patients are treated with the sequential use of two or more therapies Lancet. 2015 Sep 19;386(9999):1147-55. 55
  • 56. Limitations of currently available drugs 56
  • 57. Limitations of currently available drugs • Use of Bisphosphonates, particularly for long periods of time (5-7 years), is associated with an increased risk of atypical femoral fracture (AFF) J Bone Metab 2015;22:183-189 • Osteonecrosis of Jaw (ONJ) is a rare complication, that may occur in patients receiving high dose intravenous bisphosphonate or denosumab therapy
  • 58. • Data from Post-marketing surveillance and experimental studies found a 0.7-2.4% increase in rate of cancer with long term use of calcitonin • Risk of venous thromboembolism and stroke with raloxifene • Despite fracture risk reduction with antiresorptives, FRACTURE MAY STILL OCCUR J Obstet Gynaecol Can 2014;36(9 eSuppl C):S1–S15
  • 59. Clinical Need for Teriparatide in Osteoporosis • While current treatments [BsP, SERMs, HRT and Calcitonin] reduce fracture risk and allay bone loss, many patients remain at significant fracture risk • Current treatments are unable to restore bone matrix or architecture
  • 62. Teriparatide Injection [rhPTH(1-34)] • First [only available at present] clinically useful bone formation agent • activates osteoblasts and stimulates formation of new bone • increases bone mass (greatest increase in BMD observed at the lumbar spine) and restores skeletal architecture 62 Control Teriparatide
  • 63. Effect Of Teriparatide On Skeletal Architecture Baseline Follow up: 21 Months Treatment Jiang et al., J Bone Miner Res 2003;18:1932-40 Eriksen, Drugs Today 2004;40:935-948 Patient treated with teriparatide 20µg Female, age 65 Duration of therapy: 637 days (approx. 21 months) BMD Change: Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%) Total Hip: +5.2% (group mean = 2.6 ± 4.9%) 6 3 FOR/CYCLE2/2016/02427S1
  • 64. USFDA Approved Indication since 2002 For the treatment of Severe Osteoporosis including 1. Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture 2. Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture 3. Treatment of Men and Women with Glucocorticoid- Induced Osteoporosis at High Risk for Fracture DCGI approved indication and Forteo PI March 2012
  • 65. Teriparatide Injection [rhPTH(1-34)] • 20 µg daily subcutaneous administration. • Should not be given for more than 2 years- WHO Hepatic Impairment No studies have been performed in patients with hepatic impairment. Renal Impairment In 5 patients with severe renal impairment (CrCl<30 mL/min), the AUC and T1/2 of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased Check Ser Calcium and Ser PTH Level before starting Urolithiasis or Pre-existing Hypercalciuria If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. Teriparatide should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition.
  • 67. Teriparatide Compared to placebo and Bsp [Alendronate] 67
  • 68. Fracture Prevention Trial [FPT]: Pivotal Trial in Women • Prospective, randomized, double-blind trial performed at 99 sites in 17 countries • 1637 postmenopausal women with a prevalent vertebral fracture • Primary endpoint: Proportion of women with one or more new vertebral fractures • Teriparatide 20 µg, 40 µg, or placebo by once daily self-injection N Engl J Med 2001;344:1434-41.
  • 69. FPT: Fracture Incidence in Postmenopausal Women 69 Teriparatide d p≤0.025 compared with placebo
  • 70. FPT: Treatment with teriparatide • Reduced the risk of vertebral fractures by 65% • Reduced the risk of new multiple vertebral fractures by 77% • Reduced the risk of nonvertebral fragility fractures by 53% • Increased BMD at the spine and hip • Improved bone microarchitecture 70
  • 71. FACT: Forteo Alendronate Comparator Trial • 203 postmenopausal women with osteoporosis in an 18-month randomized parallel double-blind study compared Teriparatide vs. alendronate [10 mg] on BMD and markers of bone turnover. Arch Intern Med. 2005 Aug 8-22;165(15):1762-8. TPTD ALN At 6 months markers of bone turnover increased Decrease P<.001 At 18 months, areal spine BMDs 10.3% 5.5% [P<.001 ] At 18 months, volumetric spine BMDs 19 % 3.8 % [P<.01] Areal femoral neck BMD 3.9% 3.5% Increases in BMD by opposite mechanisms of action on bone remodeling.
  • 73. EUROFORS: European Forsteo Study • A 2-yr, prospective, controlled, randomized, open-label clinical trial of 868 postmenopausal women with established osteoporosis. • Study consisted of two substudies (1 and 2) and two treatment phases and was conducted at 95 centers in 10 European countries. • Patients were classified into three groups (1) treatment-naïve (2) pretreated with antiresorptive drugs (AR pretreated), and (3) AR pretreated with inadequate clinical outcome (inadequate AR responders). J Bone Miner Res 2008;23:1591–1600.
  • 74. EUROFORS: European Forsteo Study J Bone Miner Res 2009;24:726–736.
  • 75. EUROFORS: Substudy 1 • At 12 moths, all treatment- naı¨ve and AR pretreated participants were randomized (3:1:1) to  Continue teriparatide (treatment arm 1) [n=305],  Switch to raloxifene 60 mg/d (treatment arm 2) [n=100], or  Receive no active treatment (treatment arm 3) [n=102], for the second year 75
  • 76. EUROFORS Substudy 1 Results 76
  • 77. EUROFORS: Substudy 1 conclusion 1) A second year of teriparatide is associated with significant progressive BMD increases at both the lumbar spine and hip, 2) Sequential therapy with raloxifene after 1 yr of teriparatide maintains the BMD gains at the lumbar spine and further increases BMD at the hip, and 3) Sequential therapy with Ca and Vit D alone is associated with a partial loss of the spine BMD that was previously gained with teriparatide.  Findings indicate that raloxifene would be a suitable sequential treatment after teriparatide. Raloxifene may be of particular value in patients who use teriparatide because of an inability to tolerate bisphosphonates.
  • 78. EUROFORS: Effects of Two yrs daily TPTD Patients from Substudy 1 & 2 Examined BMD response and safety in a subgroup of 503 postmenopausal women with osteoporosis who received teriparatide for 24 mo. Treatment with teriparatide for 24 mo is associated with  Significant increases in BMD at the lumbar spine, total hip, and femoral neck, in patients with and without prior AR treatment. Prior AR treatment modestly blunted the BMD response to teriparatide.  24 months of daily teriparatide treatment results in significantly greater increases in BMD compared with an 18-mo treatment period and with a patient safety profile consistent with 18 months J Bone Miner Res 2008;23:1591–1600.
  • 81. Teriparatide: Switch or Add ??? 81 In patients previously treated with antiresorptive drugs Switch Stop the antiresorptive agent when teriparatide is initiated Add continue the antiresorptive agent when teriparatide is initiated J Bone Miner Res. 2013 Jun;28(6):1328- 36. doi: 10.1002/jbmr.1853
  • 82. Hip and spine strength effects of adding versus switching to teriparatide in postmenopausal women with osteoporosis treated with prior alendronate or raloxifene • Many postmenopausal women treated with teriparatide for osteoporosis have previously received antiresorptive therapy • In women treated with alendronate (ALN) or raloxifene (RLX), adding versus switching to teriparatide produce different responses • Postmenopausal women with osteoporosis receiving ALN 70 mg/week (n = 91) or RLX 60 mg/day (n = 77) for ≥18 months were randomly assigned to add or switch to teriparatide 20 µg/day. 82 J Bone Miner Res. 2013 Jun;28(6):1328- 36. doi: 10.1002/jbmr.1853.
  • 83. Study scheme: Add or switch 83 J Bone Miner Res. 2013 Jun;28(6):1328-36. doi: 10.1002/jbmr.1853.
  • 84. Effects of adding versus switching to teriparatide in postmenopausal women with osteoporosis pretreated with raloxifene or alendronate 84 J Bone Miner Res. 2013 Jun;28(6):1328-36. doi: 10.1002/jbmr.1853. For the spine: in patients previously treated with ALN or RLX, there were no differences in the observed increases in either integral vBMD or strength between the Add and Switch groups. For the RLX stratum, in the analysis of the hip, adding teriparatide to RLX resulted in an earlier increase in hip strength, but by 18 months there was no significant difference in the improvement in integral hip vBMD or strength in those who continued versus those who stopped RLX. In contrast, in the ALN stratum, hip vBMD increased from baseline at both 6 and 18 months only in the Add group and hip strength increased only in the Add group.
  • 85. Hip and spine strength effects of adding versus switching to teriparatide in postmenopausal women with osteoporosis treated with prior alendronate or raloxifene • Adding or switching to teriparatide conferred similar benefits on spine strength in postmenopausal women with osteoporosis pretreated with ALN or RLX. • Increases in hip strength were more variable. – In RLX-treated women, strength increased more quickly in the Add group; in ALN-treated women, a significant increase in strength compared with baseline was seen only in the Add group. 85 J Bone Miner Res. 2013 Jun;28(6):1328- 36. doi: 10.1002/jbmr.1853.
  • 86. Teriparatide: Switch or Add ??? 86 In patients previously treated with antiresorpti ve drugs ALN/RLX Switch J Bone Miner Res. 2013 Jun;28(6):1328- 36. doi: 10.1002/jbmr.1853 Add At risk of spine fracture Add or switch with Teriparatide Similar outcome At risk of Hip fracture ALN pretreated: Add Teriparatide with ALN Better outcome RLX pretreated: Add or switch with Teriparatide similar outcome
  • 88. • Teriparatide increases bone formation throughout the skeleton, including the hip and also increases hip strength • In clinical fracture-outcome trials, treatment with teriparatide has been shown to reduce the risk of nonvertebral fracture, a composite endpoint that includes hip fracture. • Body of evidence suggests that teriparatide positively affects the hip in patients with osteoporosis.
  • 89. A full 2-year course of Teriparatide treatment important to maximally increase hip BMD Similar to EUROFORS, another two studies found 1. Patients switched from alendronate to teriparatide, Total hip BMD decreased at 6 months (by 1.8%). With continued teriparatide treatment, total hip BMD increased by approximately 1.5% between months 6 and 18 2. Decrease in femoral neck BMD at 6 months followed by 2.6% increase after 12 moths with teriparatide • data indicate that patients treated with antiresorptive therapy and switched to teriparatide may experience a modest decrease in hip BMD followed by a later increase in hip BMD; for these patients, a full 2-year course of treatment with teriparatide may be important to maximally increase hip BMD.
  • 91. Combination [TPTD + antiresorptive] • Combining antiresorptive agents with PTH or TPTD is a superior hip BMD outcome compared with TPTD/PTH alone. • Most evident when TPTD/PTH is combined with a bisphosphonate or denosumab. 91
  • 92. Combination [TPTD + antiresorptive] • In contrast to findings in the hip, in the majority of studies, there is no benefit to spine BMD with combination therapy vs monotherapy. 92
  • 94. Teriparatide in Men: Pivotal Trial • ORWOLL ES et al., 2003: Prospective randomized trial performed at 34 sites in 11 countries • 437 men with idiopathic or hypogonadal osteoporosis (spine or hip T-score < -2 SD) • Primary endpoint: Change in spine BMD • Teriparatide 20 µg/day, 40 µg/day, or placebo by once-daily self-injection 94 J Bone Miner Res 2003;18:9–17
  • 95. Results: % change in BMD in lumbar spine 95 Teriparatide results in an increase in BMD and is a potentially useful therapy for osteoporosis in men J Bone Miner Res 2003;18:9–17
  • 96. Teriparatide Clinical evidence Glucocorticoid Induced Osteoporosis (GIO) 96
  • 97. Teriparatide in Glucocorticoid Induced Osteoporosis • Teriparatide vs. Alendronate – Increases in BMD with teriparatide at 18 months were 2-fold higher than those associated with alendronate (mean change from baseline 8.0% compared with 3.9%; p < 0.001) [Drugs 2008] – Similar increases in BMD from baseline were seen in the teriparatide group than in the alendronate group at 36 months; 11.0% versus 5.3% for lumbar spine, 5.2% versus 2.7% for total hip, and 6.3% versus 3.4% for femoral neck (P < 0.001 for all). [Arthritis Rheum. 2009 Nov;60(11):3346-55. doi: 10.1002/art.24879.] 97
  • 98. Teriparatide in fracture healing Growing evidence yet unapproved at present 98
  • 99. Teriparatide in osteoporotic fracture • Growing body of evidence suggest a role for Teriparatide in the management of fractures. – Studies in both normal and delayed healing models have shown improvement in callus volume and mineralisation, bone mineral content, rate of successful union and strength at fracture sites. World J Orthop 2015 July 18; 6(6): 457-461 • Animal studies show teriparatide’s role in the enhancement of fracture healing: – Administration of teriparatide seems to have a positive influence on callus formation and mechanical strength of tibial fractures in rats Injury, Int. J. Care Injured 47 S1 (2016) S36–S38 99
  • 100. Teriparatide and bone healing • Aspenberg et al.: compared teriparatide 20µg versus placebo on time to radiographic healing of distal radial fractures in postmenopausal women. – Radiographic evidence of complete cortical bridging in 3 of 4 cortices happened earlier for patients assigned to teriparatide (7.4 weeks) vs. placebo (9.1 weeks). • Numerous case series state safety & potential benefits of teriparatide use in patients recovering from fractures. – A cohort of 145 patients who had failed previous fracture healing* 93% of patients demonstrated radiographic and clinical union of their fractures with teriparatide 20µg 100 * Some form of nonunion or delayed union, or were high-risk candidates for healing acute fracture
  • 102. • Research suggests Teriparatide may improve callus volume, callus mineralisation, bone mineral content and successful union • Significant improvements in rate of successful union at the fracture site in both normal and delayed healing models has been demonstrated • Currently many United States physicians use Teriparatide “off license” for fractures and non-unions • We suggest more, well designed, human randomised controlled trials are required before Teriparatide can become a mainstream option in the management of fractures and non-unions.
  • 103. • Teriparatide Improves Fracture Healing and Early Functional Recovery in Treatment of Osteoporotic Intertrochanteric Fractures Tsan-Wen Huang, MD, Po-Yao Chuang, MD, Shih-Jie Lin, MD, Chien- Yin Lee, MD, Kuo-Chin Huang, MD, Hsin-Nung Shih, MD, Mel S. Lee, MD, PhD, Robert Wen-Wei Hsu, MD, and Wun-Jer Shen, MD • Medicine (Baltimore). 2016 May; 95(19):
  • 104. Radiographic features of teriparatide-induced healing of femoral fractures Youngwoo Kim ⁎, Chiaki Tanaka, Hiroshi Tada, Hiroshi Kanoe, Takaaki Shirai Department of Orthopaedics, Kyoto City Hospital, 1-2 Mibu, higashitakada-cho, Nakagyo, Kyoto, Japan
  • 106. • Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. • Aspenberg P, Genant HK, Johansson T, Nino AJ, See K, Krohn K, García-Hernández PA, Recknor CP, Einhorn TA, Dalsky GP, Mitlak BH, Fierlinger A, Lakshmanan MC • J Bone Miner Res. 2010 Feb; 25(2):404-14.
  • 107. • Parathyroid hormone 1-84 accelerates fracture-healing in pubic bones of elderly osteoporotic women. Peichl P, Holzer LA, Maier R, Holzer G • J Bone Joint Surg Am. 2011 Sep 7; 93(17):1583-7.
  • 108. • Review Article • Orthopedic uses of teriparatide. • Bukata SV, Puzas JE • Curr Osteoporos Rep. 2010 Mar; 8(1):28-33. • Showed the beneficial effect of teriparatide in delayed union of fractures. • Average time to resolution of symptoms and radiological healing was improved
  • 109. • Successful treatment of sternal fracture nonunion with teriparatide. • Chintamaneni S, Finzel K, Gruber BL • Osteoporos Int. 2010 Jun; 21(6):1059-63
  • 110. • Teriparatide may accelerate healing in delayed unions of type III odontoid fractures: a report of 3 cases. Rubery PT, Bukata SV • J Spinal Disord Tech. 2010 Apr; 23(2):151-5.
  • 111. My own experience Day of injury 30 days later Mrs.Parasnis 68 years old
  • 112. 30 days after starting teriparatide
  • 120. Additional Uses • Teriparatide improves bone quality and healing of atypical femoral fractures associated with bisphosphonate therapy • Cherie Ying Chiang; Roger M.D. Zebaze; Ali Ghasem-Zadeh; Sandra Iuliano-Burns; Andrew Hardidge; Ego Seeman • Bone; Volume 52, Issue 1, January 2013, Pages 360-365
  • 123. Side effects of teriparatide •Dizziness or tachycardia due to hypotension may rarely happen to some patients within 4 hours after using this medication. These symptoms may persist for a few minutes to a few hours. This side effect goes away after several doses as the body adjusts to teriparatide. •pain, redness, bruising, itching, or swelling where the medicine was injected; •leg cramps;
  • 124. •joint pain; •cough, sore throat, runny nose; •headache or neck pain; •nausea, constipation, diarrhea.
  • 125. Contra indications • Avoid teriparatide use in patients with • an increased baseline risk of osteosarcoma, • those with Paget's disease, • prior radiation therapy (external or seed implants), • unexplained elevations of alkaline phosphatase, or • in young adults with open epiphyses • Metastatic bone disease • Multiple myeloma • Hypercalcemic states • Breast feeding or pregnant mothers
  • 126. CONCLUSIONS • TREAT AGGRESSIVELY • REDUCE FRACTURE RISK • Anabolic therapy + Vit D + calcium • Follow up with anti-resorptive therapy • BE PRO-ACTIVE to IMPROVE BONE HEALTH