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Title: Osteoporosi and the role of Teriparatide


1
(No Transcript)
2
  • In 2013, sources estimate that 50 million people
    in India are either osteoporotic or osteopenic
  • 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
Indian Journal of Endocrinology and Metabolism /
Jul-Aug 2014 / Vol 18 Issue 4
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 114755

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) 246256
  • 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 TestingRecommendations
  • USPSTF/ NOF
  • ALL women 65
  • MEN gt/ 70
  • Younger postmenopausal women and men 50-70 with
    clinical RFs
  • 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. Clinicians
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 BetweenBone 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
  1. Kushida K. Clin Calcium. 20041411-17.
  2. Fogelman J, Blake GM. J Nucl Med.
    2000412015-2025.

13
Age Is a Major Risk Factorfor Fracture
AGE
80
70
60
10-Year Probability of Symptomatic Fracture ()
50
-3
-2
-1
With kind permission from Springer
ScienceBusiness Media Kanis JA ,et al. Ten year
probabilities of osteoporoticfractures according
to BMD and diagnostic thresholds. Osteoporos
Int.200112989-995. Adapted from Fig. 3. 2001
International Osteoporosis Foundation and
National Osteoporosis Foundation.
14
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 gt50 if1
  • Fracture after age 50
  • Clinical risk factors for osteoporosis
  • Conditions/medications associated with bone loss
  • COPD, RA, hyperparathyroidism, celiac disease,
    IBD
  • Oral glucocorticoids, anticonvulsants, proton
    pump inhibitors, SSRIs, aromatase inhibitors

1. Adapted from National Osteoporosis Foundation.
Clinicians 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. 2002137526-528.
15
Majority of Fractures Occur in Patients With
Osteopenia, Not Osteoporosis!
  • Why?
  • Osteopenia patients outnumber those with
    osteoporosis 31
  • Fracture riskdetermined 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. 2012102285-288.
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 gt70
  • 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
NOF Guidelines 2010Whom to Treat
After exclusion of secondary causes, treat
postmenopausal women and men age 50 and older
who have
T-scores between -1.0 and -2.5 and
Osteoporosis Clinical diagnosis Hip or spine
fracture DXA diagnosis T-score -2.5 or below
in the spine or hip
10-year risk of fractures 3 for hip fracture
or 20 for a major osteoporotic fracture
National Osteoporosis Foundation. Clinicians
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.
20
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22
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. 1. National Osteoporosis Foundation. FRAX
    Implementation Guide. Available at
    http//www.iscd.org/wp-content/uploads/2012/10/FRA
    XImplementationGuide_000.pdf . Accessed September
    13, 2013.
  2. 2. Kanis J, et al. Osteoporosis Int.
    200516581-589.

23
FRAX CaveatsEntering Bone Density Data
Use Femoral Neck Bone Mineral Density (BMD) only
Select DXA manufacturer and enter BMD (g/cm2)
24
Mrs.Deshpande- After DEXA
NOF Guidelines 20 major fx 3 hip fx
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

Specific treatment decisions must be
individualized
National Osteoporosis Foundation. Clinicians
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.
26
When Clinical JudgmentIs Needed
  • FRAX may underestimate fracture risk
  • Some risk factors (glucocorticoids, smoking,
    alcohol, fractures) are dose dependent, but FRAX
    cant 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. Clinicians
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. 2001161130-1135 Nguyen TV, et
al. J Bone Miner Res. 2005201195-1201
Sornay-Rendu E, et al. J Bone Miner Res.
2005201929-1935.
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
    decreasetreatment of low-risk patients

28
Osteoporosis Management
  • Nonpharmacologic
  • Pharmacologic

29
Challenges With Current Treatment Approaches
  • Bone loss per se asymptomatic
  • Patients may not appreciate fracture prevention
  • No treatment agent meets the ideal
    profileinexpensive, 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
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

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
34
Normal bone
35
Osteoporotic bone
36
Osteomalacic bone
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.
2001631121-1128. 2. Lenchnik L, et al. AJR.
2004183949-958.
41
TREATMENT OF OSTEOPOROSIS
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.

43
To keep bone healthy
Exercise regularly
44
Educate proper lifting techniques
45
Avoid falls
46
Calcium and Vitamin D
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

49
Raloxifene 60 mg daily
  • 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
  • Adverse effects
  • Hot flashes
  • 2- to 3-fold increased risk of venous
    thromboembolic events
  • Increased risk of death following stroke
  • Leg cramps

Ettinger B, et al. JAMA. 1999282637-645.
Sontag A, Wan X, Krege JH. Curr Med Res Opin.
20102671-76.
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. 2000109267-276.
http//effectivehealthcare.ahrq.gov/slides/?pageac
tiondisplaySlidestk49dpg9scroll314.
Accessed September 13, 2013. European Medicines
Agency. Press release. July 20, 2012. Available
at http//www.ema.europa.eu/docs/en_GB/document_l
ibrary/Press_release/2012/07/WC500130122.pdf.
Accessed September 13, 2013.
51
BisphosphonatesAlendronate, 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
    treatmentand every other year for prevention

National Osteoporosis Foundation. Clinicians
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.
2009368756-765 Prolia (prescribing
information). Thousand Oaks, CA Amgen June
2012. McClung MR, et al. Osteoporos Int.
201324(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 Sep25(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 19386(9999)1147-55.

56
Limitations of currently available drugs
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 201522183-189
  • 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 201436(9 eSuppl C)S1S15

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

60

Teriparatide In Osteoporosis
61
Teriparatide
  • Drug Profile

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

Control
Teriparatide
63
Effect Of Teriparatide On Skeletal Architecture
Follow up 21 Months Treatment
Baseline
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)
Jiang et al., J Bone Miner Res 2003181932-40 Eri
ksen, Drugs Today 200440935-948
FOR/CYCLE2/2016/02427S1
64
USFDA Approved Indication since 2002
  • For the treatment of Severe Osteoporosis
    including
  • Treatment of Postmenopausal Women with
    Osteoporosis at High Risk for Fracture
  • Increase of Bone Mass in Men with Primary or
    Hypogonadal Osteoporosis at High Risk for
    Fracture
  • 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 (CrCllt30 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.
66
Teriparatide
  • Evidence

67
Teriparatide
  • Compared to placebo and Bsp Alendronate

68
Fracture Prevention Trial FPTPivotal 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 20013441434-41.
69
FPT Fracture Incidence in Postmenopausal Women
d p0.025 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

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.

TPTD ALN
At 6 months markers of bone turnover increased Decrease Plt.001
At 18 months, areal spine BMDs 10.3 5.5 Plt.001
At 18 months, volumetric spine BMDs 19 3.8 Plt.01
Areal femoral neck BMD 3.9 3.5
Increases in BMD by opposite mechanisms of action
on bone remodeling.
Arch Intern Med. 2005 Aug 8-22165(15)1762-8.
72
Teriparatide
  • After Antiresorptive

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 20082315911600.
74
EUROFORS European Forsteo Study
J Bone Miner Res 200924726736.
75
EUROFORS Substudy 1
  • At 12 moths, all treatment- naive and AR
    pretreated participants were randomized (311)
    to
  • Continue teriparatide (treatment arm 1) n305,
  • Switch to raloxifene 60 mg/d (treatment arm 2)
    n100, or
  • Receive no active treatment (treatment arm 3)
    n102, for the second year

76
EUROFORS Substudy 1 Results
77
EUROFORS Substudy 1 conclusion
  • A second year of teriparatide is associated with
    significant progressive BMD increases at both the
    lumbar spine and hip,
  • 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
  • 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 20082315911600.
79
FOR/CYCLE2/2016/02427S1
80
Teriparatide
  • Used as Switch or Add ?

81
Teriparatide Switch or Add ???
Switch Stop the antiresorptive agent when
teriparatide is initiated
In patients previously treated with
antiresorptive drugs
Add continue the antiresorptive agent when
teriparatide is initiated
J Bone Miner Res. 2013 Jun28(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.

J Bone Miner Res. 2013 Jun28(6)1328-36. doi
10.1002/jbmr.1853.
83
Study scheme Add or switch
J Bone Miner Res. 2013 Jun28(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
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.
J Bone Miner Res. 2013 Jun28(6)1328-36. doi
10.1002/jbmr.1853.
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.

J Bone Miner Res. 2013 Jun28(6)1328-36. doi
10.1002/jbmr.1853.
86
Teriparatide Switch or Add ???
At risk of spine fracture Add or switch with
Teriparatide Similar outcome
Switch
In patients previously treated with
antiresorptive drugs ALN/RLX
At risk of Hip fracture ALN pretreated Add
Teriparatide with ALN Better outcome RLX
pretreated Add or switch with Teriparatide
similar outcome
Add
J Bone Miner Res. 2013 Jun28(6)1328-36. doi
10.1002/jbmr.1853
87
Teriparatide
  • Literature review Teriparatide 20 µg/day at Hip

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
  • 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
  • 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.

90
Teriparatide
  • In combination

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.

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.

93
Teriparatide
  • In Men

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 lt -2 SD)
  • Primary endpoint Change in spine BMD
  • Teriparatide 20 µg/day, 40 µg/day, or placebo by
    once-daily self-injection

J Bone Miner Res 200318917
95
Results change in BMD in lumbar spine
Teriparatide results in an increase in BMD and is
a potentially useful therapy for osteoporosis in
men
J Bone Miner Res 200318917
96
Teriparatide Clinical evidence
  • Glucocorticoid Induced Osteoporosis (GIO)

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 lt 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 lt 0.001 for all).
    Arthritis Rheum. 2009 Nov60(11)3346-55. doi
    10.1002/art.24879.

98
Teriparatide in fracture healing
  • Growing evidence yet unapproved at present

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 teriparatides 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) S36S38

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

Some form of nonunion or delayed union, or were
high-risk candidates for healing acute fracture
101
Teriparatide in fracture healing
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
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  • 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.

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My own experience
Day of injury
30 days later
Mrs.Parasnis 68 years old
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30 days after starting teriparatide
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Mr.Broachwala- 66 yearsOld
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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

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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

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  • 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

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CONCLUSIONS
  • TREAT AGGRESSIVELY
  • REDUCE FRACTURE RISK
  • Anabolic therapy Vit D calcium
  • Follow up with anti-resorptive therapy
  • BE PRO-ACTIVE to IMPROVE BONE HEALTH

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