UPDATE ON

OSTEOPOROSIS

DR. SALIHA ISHAQ, MBBS, MD.

American Board of Internal Medicine & Rheumatology.
Assistant Professor
Department of Medicine
Aga Khan University Hospital
 Impact

 Chronic pain
 Height loss
 Kyphosis
 Decreased self-
esteem
 Restrictive lung dx
 Constipation,
abdominal pain
 Depression
 Osteoporosis Is a Chronic,
Progressive Disease with
Potentially Serious
Consequences
 Women with
postmenopausal
osteoporosis can
have fractures with
minimal trauma1
– 1 in 2 women > 50 will
experience an osteoporotic
fracture in their remaining
lifetime2
– In 2005, incidence of
osteoporotic fractures in women
≥ 50 was more than 1.4 million3
– 1 in 5 patients who have a
hip fracture will die within a
year4
Image courtesy of Geoffrey B. Higgs, MD.
1. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2008
2. US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. 2004.
5 3. Burge R, et al. J Bone Miner Res. 2007;22:465-475.
4. Johnell O, et al. Osteoporos Int. 2004;15:38-42.
4 of 45
 Risk Factors for
Osteoporosis
Non-modifiable
 Age
 Race (Caucasian, Asian)
 Female gender
 Early menopause (<45
y/o)
 Slender build (<127 lbs)
 Positive family history
Modifiable
 Low calcium intake
 Low vitamin D intake
 Estrogen/androgen
deficiency
 Sedentary lifestyle
 Cigarette smoking
 Alcohol excess (>2
drinks/day)
 Caffeine excess (>
cups/day)
 Medications
(glucocorticoids,
anticonvulsants,excess
thyroxine)
 Classification
 Primary
 Postmenopausal
 Decreased estrogen results in increased osteoclastic
activity without increased osteoblastic activity
 Bone loss – 2-3% per year of total bone mass (over a
life time a women may loose up to 40% of her peak
bone mass.)
 Most common fx: vertebral, distal forearm

 Age related – 3rd decade of life starts slow

decline in bone mass at rate of 0.5-1% per year
 Most common types of fx: hip and radius
 F>M

8
 Bone Mass in Women
Over the Lifecycle
Attainment of
Peak bone mass Menopaus Bone loss
peak bone mass
e
100
Percent Peak Bone Mass

80

60

40

20

Formation > Resorption Resorption > Formation

0 10 20 30 40 50 60 70 80
9 Age (years)
 Bone Growth Overtime

Graphic used with permission from The 2004 Surgeon General’s Report on Bone Health and Osteoporosis: What It Means To You.
 Secondary Osteoporosis
Disease states

 Acromegaly
 Multiple myeloma
 Addison’s disease  Multiple sclerosis
 Amyloidosis  Rheumatoid
 Anorexia
arthritis
 COPD
 Hemochromatosis  Sarcoidosis
 Hyperparathyroidism  Severe liver dz,
 Lymphoma and esp. PBC
leukemia
 Malabsorption states
 Thalessemia
(Celiac sprue)  Thyrotoxicosis

11
 Secondary
Osteoporosis
Drugs
 Aluminum  Glucocorticoids
 Anticonvulsants  GnRH agonists
 Excessive alcohol)  Heparin
(more than 3 units a  Lithium
day)
 Excessive thyroxine

 Depo Provera
(decreased bone mass
reversible after
stopping medication)

12
 World Health Organization
(WHO) Definition
Based on BMD testing
 Normal: T score above –1

 Osteopenia: T score between –1 and –2.5

 Osteoporosis: T score at or below –2.5

 Severe osteoporosis: T score –2.5 or

lower in the presence of 1 or more
fractures

13
 Types of BMD testing
 Dual –energy x-ray absorptiometry (DXA or DEXA).
 Gold Standard
 Measures BMD in spine, hip, or wrist
 Completed in a few minutes
 Radiation exposure less than 1/10 of standard x-ray
 Ultrasound densitometry
 No radiatiation exposure
 Measures BMD in heel, patella
 Cost-effective
 Poor correlation between US and DXA
 Inconsistent young normal reference populations may contribute
 Single-energy x-ray absorptiometry and peripheral dual x-ray
 Quantitative computed tomography (QCT)
 Radiographic absorptiometry

14
 When to perform a bone density
test
National Osteoporosis
Foundation (NOF) Guidelines

 All postmenopausal women under age 65 who

have one or more additional risk factors for
osteoporotic fx (besides menopause)

 All woman aged 65 and older regardless of

additional risk factors

 Postmenopausal women who present with

fractures

 All men above the age of 70

15
 Available Medications for
Postmenopausal
Osteoporosis
Antiresorptive Agents1
Oral and IV
Estrogen*
Bisphosphonates
Estrogen
Calcitonin
Agonist/Antagonist

Anabolic Agent1
PTH analog

Oral bisphosphonates are the most commonly used

pharmacologic agents for osteoporosis management2
*Indicated for prevention only; PTH = parathyroid hormone
16 1. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis.
2008.
2. IMS Health NSP Data. Analysis of PMO product basket. January 2009.
 Treatment
Preventive Measures
 Calcium
 Vitamin D (400-800 IU)
 Regular weight bearing
exercise
 Weight lifting, salsa
dancing, walking, jogging,
tennis
 Smoking cessation
 Minimize alcohol intake
 Fall prevention esp for
elderly

17
 NATIONAL OSTEOPOROSIS
FOUNDATION:
UPDATED RECOMMENDATIONS

Recommended Intake for Adults ≥50 Years

Calcium Vitamin D3
(mg/day) (IU/day)

Previous (2003) 1200 400–800

Current update 1200 800–1000

“NOF revised its recommendations after careful consideration and review of a growing body of
evidence that calcium and vitamin D3 deficiency is widespread throughout the world as well as in
the US, particularly in adults 50 and older.”
—NOF Scientific Statement, Revised October 2008

Adapted from National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. National Osteoporosis Foundation, 2003; National Osteoporosis
Foundation. National Osteoporosis Foundation’s updated recommendations for calcium and
vitamin D intake. Available at: www.nof.org/prevention/calcium_and_VitaminD.htm. Accessed 26 January 2009.
 Sources of Calcium
 Dietary
– 8oz milk or yogurt = 300mg
– 2oz cheese = 400mg
 Calcium carbonate – Ingest with meals
– Generic = 200-600mg
– Caltrate = 600mg
– TUMS Ultra = 400mg
 Calcium citrate
– Citrical = 500mg
 Calcium gluconate
– Generic = 60mg
* All above values represent mg of elemental calcium

19
CALCITONIN NASAL SPRAY THERAPY
PREVENT RECURRENCE OF OSTEOPOROTIC
FRACTURES(PROOF)

Number of patients
Mean Age
Study Design
Drug
Calcium/Vitamin D
% with Prevalent VFx
Primary Endpoint
1255 : Most patients had 1–5 Vertebral Fx at baseline (n = 926 of 1
378 actually completed the study
68 (postmenopausal)
5 year, randomized, double-blind, placebo-controlled
Placebo (n = 311), 100 IU (n = 316), 200 IU
(n = 316, marketed dose) or 400 IU (n = 312) Calcitonin
1000 mg/400 IU daily
79%
Spine BMD and new VFX in patients with
low bone mass (T < –2.0) and 1–5 new VFX

Chesnut et al: AJM 2000, Vol 109, 267-276

 PROOF
EFFECT OF NASAL CALCITONIN ON RISK OF
VERTEBRAL FRACTURES

Women withDecreased
Dose new fractures risk p<0.05?
Placebo 26% -
100 IU 22% 15% No
200 IU 18% 33% Yes
400 IU 22% 16% No

Lost 59% of participants to follow-up!

Chesnut et al: AJM 2000, Vol 109, 267-276

 Treatment
Estrogen Replacement Therapy
(ERT)

 Indication: Used to prevent and treat

osteoporosis (FDA indication is for prevention)
 Mechanism: Decreases osteoclast activity
 Dose: Estrogen: 0.625mg qd, 0.3mg offers bone
protection as well; Progesterone 2.5mg qd (if
uterus present)
 HRT

 Advantages  Disadvantages
 Increases bone
density (1-5%) and
decreases risk of
fracture (25%)
 Relief of hot flashes,
vaginal dryness
 Decreases LDL,
increases HDL
 ?Prevention of
Alzheimer’s disease
 Relatively
inexpensive
 Accelerated bone loss after
stopping
 Increased risk of uterine ca
(if unopposed)
 Increased risk of
thromboembolic events
 Possible increased risk of
breast cancer
 Side effects: breast
tenderness, breakthrough
bleeding
 Increased risk of
coronary events in
women with known CAD
in first year of use
(HERS trial)
RALOXIFENE
 EVALUATING THE EVIDENCE:
RALOXIFENE
MULTIPLE OUTCOMES OF RALOXIFENE EVALUATION
(MORE)

Number of Patients 7705 patients (2 subgroups)

Substudy 1 = 5064 with hip or spine T-score ≤ –2.5 Substudy 2 =
2641 with prior VFX
Mean Age 67 (postmenopausal)
Mean FN T-Score -3.2 SDs
Study Design 3 year, randomized, double-blind, placebo-controlled
Drug 60 mg (marketed dose) or 120 mg raloxifene
Calcium/Vitamin D 500 mg/400 IU daily
Primary Endpoint VFX and non-VFX in patients with low bone mass (T-score < –2.5)
or radiographic VFX

JAMA, August 18, 1999--Vol 282, No. 7, pp 637-645

Effect of Raloxifene in Women with
or Without Pre-Existing Fractures
MORE Trial—3 Years
25 RR 0.7a
Incident Vertebral Fractures Placebo (95% CI = 0.6–0.9)
Raloxifene 60 mg/d
20
% of Women with

30%

15

10
RR 0.5a
(95% CI = 0.3–0.7)

5
55%

0
Without Pre-Existing With Pre-Existing
Vertebral Fracture Vertebral Fracture
a
Women who completed the study and had evaluable radiographs at 36 months.
With permission from Ettinger B, et al. JAMA. 1999;282:637-645.
Available Bisphosphonates for
Osteoporosis FDA Approved

 Oral

– Alendronate (daily, weekly)

– Risedronate (daily, weekly, monthly)
– Ibandronate (daily, monthly)
 Intravenous
– Ibandronate (quarterly)
– Zoledronic acid (annual)
 Off-label
– Pamidronate (IV quarterly)
ALENDRONATE
 THE FRACTURE INTERVENTION
TRIAL (FIT):
A LANDMARK STUDY IN OSTEOPOROSIS

 First comprehensive fracture study in postmenopausal women with

bone mass
(T < -1.6): with and without existing vertebral fracture

 Specifically designed to investigate the effect of alendronate on the

reduction in the risk of fractures:
– vertebral (symptomatic and morphometric)
– any symptomatic
– any non-vertebral
– hip
– forearm

FIT = Fracture Intervention Trial.

a
Significant cumulative difference from placebo (P<0.05).
Adapted from Black DM, et al. J Clin Endocrinol Metab. 2000;85:4118–4124..
 EVIDENCE OF EARLY EFFICACY AT
THE SPINE
ALENDRONATE: FRACTURE INTERVENTION TRIAL
COMBINED ANALYSIS1

Clinical (Symptomatic) Vertebral Fractures

4
PBO (n = 1817)
§

% of Patients with Fracture

ALN 5/10 mg (n = 1841)
§
N = 3658
3
Age = 55 to 80 years §
Patients with preexisting
VFx’s or FN BMD 59%
T-score < –2.5 at baseline 2 Reduction §
§

1
§ P < 0.030

0
0 6 12 18 24 30 36
Months
J Bone Miner Res. 1999 Supplement.
 FIT TRIAL - Summary of
Fracture Results
Type of fracture % incidence
P value
reduction
At least one new
vertebral fracture 47
<0.001
Multiple (>2) new
vertebral fractures 90
<0.001
Clinical (symptomatic)
vertebral fracture 55
Lancet, 348, 1996 <0.001
 ALENDRONATE PROVIDED SUSTAINED
IMPROVEMENT IN BMD OVER 10 YEARS
14
Alendronate10 mg daily Spine 13.7%
(P<0.001)
12

Hip Trochanter 10.3%

10 (P<0.001)

8
Total Hip 6.7%
(P<0.001)
6

4
e gna h C %) ES±( nae M

0 1 2 3 4 5 6 7 8 9 10

n=196 n=151 n=122 n=86

BMD = bone mineral density.

Year
Adapted from Bone HG, et al. N Engl J Med. 2004;350:1189–1199.
FOSAMAX™ (alendronate) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
 RESIDRONATE
 RISEDRONATE VERTEBRAL FRACTURE
STUDIES1,2

 NORTH AMERICAN STUDY1  INTERNATIONAL STUDY2

• n = 2,458 • n = 1,226
• Mean Age = 69 • Mean Age = 71
• Mean FN T-score = –2.7 • Mean LS T-score = –2.8
• % w/ VFx at baseline = 100% • % w/ VFx at baseline =
• Mean VFx at baseline = 2.5 100%
• Median VFx at baseline = 3-
4

1. Harris ST. JAMA. 1999;282(14):1344-1352

2. Reginster JY. Osteo Int. 2000;11:83-91
Antifracture efficacy of Risedronate
over time
41% Year 3

55% Year 2

65% Year 1

0.25 0.5 0.75 1

New Morphometric Vertebral Fractures

Risedronate USPI
Harris ST, et al. JAMA 1999;282:1344–52
 IBANDRONATE
 Meta-analysis compares
dose
groups defined by ACE*
compared
Higher doses with Lower dose
(ACE 10.8–12mg) (ACE 5.5mg)

Monthly oral† Quarterly IV 3mg

150mg

Daily oral† 2.5mg

Bimonthly i.v. 2mg

NOT LICENSED

*ACE = annual cumulative exposure = dose x doses/year x absorption (e.g. 2.5 x 365 x 0.6% = 5.5mg ACE)
†
Absorption for oral ibandronate = 0.6%1
1
Barrett J, et al. J Clin Pharmacol 2004;44:951–65
 Daily ibandronate
reduces vertebral
10
fracture risk
Fracture rate at 3 years (%)

8 62% RRR
(p=0.0001
vs placebo)
6

0 Placebo Daily
ibandronate
Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9
 Fast and consistent
efficacy of Ibandronate
over time
62% Year 3

61% Year 2

58% Year 1

0.25 0.5 0.75 1

Relative risk (95% CI) for new vertebral fractures

 Zoledronic acid
Zoledronic acid /Horizon
trial

 In a 3 year trial ,once yearly treatment reduced

– Risk of vertebral fractures by 70% compared with
placebo
– Risk of hip fracture 41%compared with placebo

– Bone mineral density increased by 7% at spine

– -Total hip Bone density increased by about 5.1%

– All three biochemical markers of bone turnover

decreased significantly as compared with the
placebo group
HORIZON TRIAL
 FRACTURE RISK REDUCTION BY
BISPHOSPHONATES*

Data not from comparative trials

Relative Risk Reduction (95% CI)
Fracture Type Alendronate1 Risedronate1 Ibandronate2 Zolendronate3
Vertebral 44% 39% 50% 70%
(32 to 54%) (25 to 50%) (26 to 66%) (62 to 77%)

Hip 38% 26% NS 41%

(2 to 60%) (7 to 41%) (17 to 58%)

Wrist 33% 32% NS 19%

(-31 to 66%) (-8 to 57%) (-6 to 38%)

Other Non- 19% 24% NS 25%**

Vertebral (3 to 32%) (9 to 36%) (13 to 36%)

NS = non-significant, * Data not from comparative trials, ** Includes wrist and hip fracture results

1. Stevenson M, et al (2006) Analyses of the cost-effectiveness of pooled alendronate and risedronate, compared with strontium
ranelate, raloxifene, etidronate and teriparatide. Sheffield: School of Health and Related Research (ScHARR))
2. Chesnut CH, et al. Curr Med Res Opin. 2005;21(3):391–401. 3. Black DM, et al. N Engl J Med. 2007;356:1809-1822.
OSTEOPOROSIS TREATMENT IN
2009
SUMMARY

• HRT: no prospective fracture data

• SERMS: spine fx; No effect on peripheral fx
• Calcitonin: possible spine fx; No hip data
• Vitamin D analogues: possible spine fx; No hip data
• Alendronate:  spine fx ≅ 50%;  hip fx ≅ 50%
• Risedronate:  spine fx ≅ 50%;  hip fx ≅ 30%
• Ibandronate:  spine fx ≅ 50%;  hip fx ≅ No hip fx
reduction
• Zolendronic :  spine fx ≅ 70;  hip fx ≅ 40%
TERIPERITIDE
 Intermittent PTH administration
increased vertebral and femoral
bone density

PTH (20 µg) PTH (40 µg)

Spine 9 .7 % 1 3.7 %
Hip 2 .8 % 5 .1 %
 Percent change from baseline over a 19 month
followup period (length of randomization)
 Basic Lab Tests Before
Starting Teriparatide
 Serum calcium
 Alkaline phosphatase
 25 hydroxy-vitamin D
 PTH
 Serum creatinine

Miller PD, et al. Endocrine Practice. 2004;10:139–148.

 Decrease in the risk of
vertebral and non vertebral
fractures

PTH PTH
(20 µg) (40 µg)
One or more
65 % 69 %
new vertebral
fracture
Non vertebral
35 % 40 %
fractures

 Significant risk reduction of new vertebral fractures (vs

placebo)
 Significant risk reduction of new non vertebral fractures
 Effect of Teriparatide on Risk of
Vertebral Fractures in
Postmenopausal Women
16 RR 0.35 (95% CI = 0.22–0.55)a
14
% of Patients with ≥1 Fracture

12

10

8
65% ↓
6

0
Placebo Teriparatide 20 µg
a
P <.001 vs placebo.
Neer RM, et al. N Engl J Med. 2001;344:1434-1441.
Graphic courtesy of Dr. Paul Miller.
 FDA-APPROVED
MEDICATIONS
INDICATIONS

Postmenopausal Glucocorticoid-induced Men

Osteoporosis Osteoporosis
Drug Prevention Treatment Prevention Treatment

Estrogen 
Calcitonin 
(Miacalcin®, Fortical®)

Raloxifene  
(Evista®)
Ibandronate  
(Boniva®)
Alendronate     
(Fosamax®)
Risedronate     
(Actonel®)
Zoledronic acid 
(Reclast®)
Teriparatide  
(Forteo®)
www.fda.gov
 OSTEOPOROSIS TREATMENT IN
2009
SUMMARY

• HRT: no prospective fracture data

• SERMS: spine fx; No effect on peripheral fx
• Calcitonin: possible spine fx; No hip data
• Vitamin D analogues: possible spine fx; No hip data
• Alendronate:  spine fx ≅ 50%;  hip fx ≅ 50%
• Risedronate:  spine fx ≅ 50%;  hip fx ≅ 30%
• Ibandronate:  spine fx ≅ 50%;  hip fx ≅ No hip fx reduction
• Zolendronic :  spine fx ≅ 65%;  hip fx ≅ 40%
 Indications for IV - 1
 Inability to take oral bisphosphonate
– Can’t swallow tablets
– Poor compliance with dosing instructions
– Poor adherence/persistence in general
– Cognitive impairment
 Patient preference
 Perhaps in context of polypharmacy
 “Treatment failures”
– Eg decreasing bone densities and further
fractures
 Pro’s and Con’s of Available Osteoporosis Therapies

Agent Pro’s Con’s

Calcium/Vit D Cheap, accessible Partial efficacy

HRT Effective ↑breast ca, ↑DVT, ↑MI, ↑CVA

Raloxifene ↓ vert Fx, ↓ breast ca Less effect on BMD

Bisphosphonates ↓ vert and nonvert Fx GI intolerance

Strontium Bulky, daily dosing ? Mechanism

Teriparatide Effective Expensive, daily injections

 For More Information on
Osteoporosis
American Dietetic Association
Phone: (800) 877-1600
Website: www.eatright.org

Michigan Public Health Institute- Osteoporosis Program

Phone: (517) 324-8363 Website:
www.michiganosteoporosisconnection.org

National Osteoporosis Foundation

Phone: (800) 223-9994
Website: www.nof.org

National Dairy Council

Website: www.nationaldairycouncil.org

National Institutes of Health Osteoporosis and Related Bone Disease~National Resource

Center
Phone: (800) 624-2663
Website: www.osteo.org

More information about the Surgeon General’s Report on Bone Health and Osteoporosis is
available on the Surgeon General’s website at: www.surgeongeneral.gov
 Other Changes
“Fall-proof” your home

Graphic used with permission from The 2004 Surgeon General’s Report on Bone Health and Osteoporosis: What It Means To You.
Future Treatment and Prevention
of Osteoporosis and Fractures:
 New and Emerging
Treatments
Antiresorptive (anticatabolic) Osteo-anabolic (bone-forming)
 Denosumab
 Sclerostin inhibitor
 Odanacatib
 Variations of PTH
 Endogenous PTH stimulation
 Lasofoxifene
– calcium sensing receptor
 Bazedoxifene antagonist (calcilytic)
 CE/bazedoxifene  New delivery systems –
 New delivery systems – transdermal PTH
oral salmon calcitonin

Strontium ranelate
Combinations of antiresorptive and anabolic
Denusomab: Prolia
Its an anti RankL drug approved by FDA for post menopausal
Osteoporosis.

AntiSclerostin:
Sclerostin is produced by Osteocytes of a person who has
inactive lifestyle. It blocks the of Wntβ / Catenin pathway,
so reduced the bone formation. Anti sclerostin is soon
available for Osteoporosis treatment.

Anti Cathepsin K: Baticalib

Cathepsin K is an Enzyme produced by Osteoclast, necessary
for bone resorption. Anti Cathepsin K is an oral drug
 Denosumab (Dmab)

 Fully human monoclonal antibody-IgG2 isotype

 High affinity and specificity for human RANK ligand
 Does not bind to TNFα, TNFβ, TRAIL, or CD40L
 Pharmacokinetics (SC): similar to other fully human IgG2
monoclonal antibodies
– Absorption is rapid and prolonged (Cmax ≈1–4 wks postdose)
– Long half-life ≈34 days with maximum dose
– Distribution ≈ intravascular volume
– Clearance ≈ reticuloendothelial system
– No kidney filtration or excretion of intact molecule

Abbreviations: TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand.

Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066. Boyle WJ, et al. Nature. 2003;423:337-342.
 New SERMs for Postmenopausal
Osteoporosis

 Efficacy
–
 Efficacy
Increases BMD
– Reduces BTMs – Increases BMD
– Decreases risk of VFs and NVFs – Reduces BTMs
– Decreases risk of ER+ breast – Decreases risk of VFs
cancer
– Improves signs and symptoms  Safety
of vulvovaginal atrophy – Increases risk of VTEs, hot
 Safety flushes, muscle cramps
– Increases risk of venous
thromboembolisms (VTEs), hot
flushes, muscle spasm, and
vaginal bleeding

Cummings SR, et al. J Bone Miner Res. 2008;23:S81. Silverman SL, et al. J Bone Miner Res.
2008;23:1923-1934. Eastell R, et al. J Bone Miner Res. 2008;23:S81.
THANK YOU