This document discusses osteoporosis management and the efficacy and safety of bisphosphonates. It begins with an overview of the burden of osteoporosis, noting that over 2.5 million people in Indonesia have osteoporosis and over 88 million have osteopenia. It then reviews screening and treatment guidelines before focusing on bisphosphonates. The document discusses the efficacy of various bisphosphonates at reducing fractures based on clinical trials. It also reviews controversial issues associated with long-term bisphosphonate use such as osteonecrosis of the jaw, atypical fractures, atrial fibrillation, and esophageal cancer. It concludes by noting that annual zoledronic acid injections can significantly reduce hip,

1. Osteoporosis ManagementOsteoporosis Management
Efficacy and safety of bisphosphonates

2. Today’s talk :Today’s talk :
 Burden of the disease.Burden of the disease.
 Screening and treatment guidelines.Screening and treatment guidelines.
 Bisphosphonates.Bisphosphonates.
 Once yearly bisphoshonateOnce yearly bisphoshonate
 Controversial topics : Association ofControversial topics : Association of
bisphosphonates withbisphosphonates with
 ONJONJ
 Atypical femoral fracturesAtypical femoral fractures
 Atrial fibrillation.Atrial fibrillation.
 Esophageal cancer.Esophageal cancer.

3. Classic presentation

4. Burden of DiseaseBurden of Disease
2.52.5 million people in Indonesiamillion people in Indonesia
have Osteoporosishave Osteoporosis
88 million people in Indonesiamillion people in Indonesia
have Osteopenia.have Osteopenia.

5. Burden of DiseaseBurden of Disease
> 0,5 million> 0,5 million
fractures/year due to either.fractures/year due to either.
75,00075,000 HIP fractures.HIP fractures.
150,000150,000 vertebral fractures.vertebral fractures.
35,00035,000 pelvic factures.pelvic factures.
Bone health and osteoporosis: Department ofBone health and osteoporosis: Department of

6. Burden of Disease :Burden of Disease :
Hip fracturesHip fractures ::
50 %50 % Permanent impairedPermanent impaired
mobility.mobility.
25 %25 % Loose skills to liveLoose skills to live
independently.independently.
Increased all cause mortality : firstIncreased all cause mortality : first 33
monthsmonths after hip fracture.after hip fracture.
1.2010 position statement of the North American Menopause Society. Menopause 2010.1.2010 position statement of the North American Menopause Society. Menopause 2010.

7. Annual incidenceAnnual incidence

8. Etiology of Bone loss in OsteoporosisEtiology of Bone loss in Osteoporosis
OSTEOCLAST - RESORPTIONOSTEOBLAST - FORMATION
Primary cause is estrogen deficiency
+

9. OsteoporosisOsteoporosis

10. Risk factorsRisk factors

11. Vertebral Fractures
Semi-quantitative reading / visual scoring
Genant et al., J Bone Miner Res 1993, 8:137
Normal
(Grade 0)
Wedge fracture Biconcave fracture Crush fracture
Mild fracture
(Grade 1, ~20-25%)
Moderate fracture
(Grade 2, ~25-40%)
Severe fracture
(Grade 3, ~40%)

12. Who to screenWho to screen
 Women > 65 years.Women > 65 years.
 Men > 70 years.Men > 70 years.
 Postmenopausal women /men >50 yearsPostmenopausal women /men >50 years
with clinical risk factors.with clinical risk factors.
 H/o fracture at age > 50 years.H/o fracture at age > 50 years.
 Chronic steroid use.Chronic steroid use.

13. Direct measurement of BMD by DXA and
as well as CT allows us to diagnose osteopenia

14. DXA

16. Fracture risk calculationFracture risk calculation

17. Who to treat ?Who to treat ?
Prior h/o hip/vertebral #Prior h/o hip/vertebral #
oror
T Score < -2.5T Score < -2.5
oror
T Score -1 to -2.5 &
10 yr risk (FRAX) :
HIP # > 3 % or
major osteoporotic # > 20 %
T Score -1 to -2.5 &
10 yr risk (FRAX) :
HIP # > 3 % or
major osteoporotic # > 20 %
Postmenopausal women /men > 50 yrs
with

18. Recommendation for women and men > 50 yoRecommendation for women and men > 50 yo
•• Counsel on the risk of osteoporosis and related fractures.Counsel on the risk of osteoporosis and related fractures.
•• Advise on a diet rich inAdvise on a diet rich in fruits and vegetablesfruits and vegetables and that includesand that includes
adequate amounts of totaladequate amounts of total calcium intakecalcium intake (1,000 mg per day(1,000 mg per day
for men 50-70; 1,200 mg per day for women 51 and olderfor men 50-70; 1,200 mg per day for women 51 and older
and men 71 and older).and men 71 and older).
•• Advise onAdvise on vitamin Dvitamin D intake (800-1,000 IU per day), includingintake (800-1,000 IU per day), including
supplements if necessary for individuals age 50 and older.supplements if necessary for individuals age 50 and older.
•• Recommend regularRecommend regular weight-bearing and muscle-strengtheningweight-bearing and muscle-strengthening
exercise to improve agility, strength, posture and balance andexercise to improve agility, strength, posture and balance and
reduce the risk of falls and fractures.reduce the risk of falls and fractures.

19.  ••AssessAssess risk factorsrisk factors for falls and offerfor falls and offer
appropriate modifications :appropriate modifications :
 home safety assessment,home safety assessment,
 balance training exercises,balance training exercises,
 correction of vitamin D insufficiency,correction of vitamin D insufficiency,
 avoidance of certain medications andavoidance of certain medications and
 bifocals use when appropriatebifocals use when appropriate

20. Calcium and vitamin DCalcium and vitamin D

21. Anti-resorptive
Anabolic
‘Dual action’

22. Bone marrow precursorsBone marrow precursors
OsteoblastsOsteoblasts
OsteoclastOsteoclast
Lining cellsLining cells
Stimulators ofStimulators of
Bone FormationBone Formation
FluorideFluoride
PTH analogsPTH analogs
Sr Ranelate (?)Sr Ranelate (?)
Inhibitors ofInhibitors of
Bone ResorptionBone Resorption
Estrogen, SERMsEstrogen, SERMs
BisphosphonatesBisphosphonates
CalcitoninCalcitonin
Inhibitors of
RANKL
Cathepsin K
Therapeutic strategiesTherapeutic strategies

23. Treatments & Efficacy
Vertebral Fx Non-vertebral Fx
Other Fx Hip Fx
Oral
HRT Yes Yes Yes
Etidronate* Yes
Alendronate* Yes Yes Yes
Risedronate* Yes Yes Yes
Ibandronate* Yes [Yes]
Raloxifene* Yes
Calcitriol* Yes
Strontium Ranelate* Yes Yes [Yes]

24. Vertebral Fx Non-vertebral Fx
Other Fx Hip Fx
Subcutaneous
Teriparatide* Yes Yes
1-84 PTH* Yes
Denosumab* Yes Yes Yes
Intravenous
Pamidronate
Ibandronate*
Zoledronate* Yes Yes Yes
Intranasal or Subcutaneous
Calcitonin* Yes

25. Vertebral Fx Nonvertebral Fx
Other Fx Hip Fx
Alendronate* Yes Yes Yes
Risedronate* Yes Yes Yes
Zoledronic acid* Yes Yes Yes
PTH* Yes Yes ???
Strontium ranelate* Yes Yes ???
Denosumab* Yes Yes Yes
Appropriate use of appropriate treatmentsAppropriate use of appropriate treatments
can halve the incidence of fracturescan halve the incidence of fractures
* plus calcium + vitaminD

26. Mainstay ofMainstay of treatmenttreatment ::
BisphosphonatesBisphosphonates
Approval in US for osteoporosisApproval in US for osteoporosis
 Alendronate : 1995Alendronate : 1995
 Risedronate : 2000Risedronate : 2000
 Ibandronate : 2005Ibandronate : 2005
 Zoledronate : 2007.Zoledronate : 2007.

27. ContraindicationsContraindications

28. Duration of treatmentDuration of treatment

29. Cost factorCost factor
 Alendronate: $4 -Alendronate: $4 -
$40/month$40/month
 Risedronate : $60 -Risedronate : $60 -
$120/month$120/month
 Ibandronate (oral):Ibandronate (oral):
$90 - $130/month$90 - $130/month
 IV Ibandronate :IV Ibandronate :
$1300/year$1300/year
 IV Zoledronate :IV Zoledronate :
$1300/year$1300/year

30. Hot topicsHot topics

31. Osteonecrosis of jawOsteonecrosis of jaw

32. ONJONJ
Osteoporosis :Osteoporosis :
 Reporting rate 1/100,000 - 1/250.000.Reporting rate 1/100,000 - 1/250.000.
 True incidence may be higher.True incidence may be higher.
 Malignancy/skeletal metastasis :Malignancy/skeletal metastasis :
 Estd. Incidence: 1- 10 %Estd. Incidence: 1- 10 %

33. Risk factorsRisk factors

34. RecommendationsRecommendations

35. Atypical fracturesAtypical fractures

37. Atypical fracturesAtypical fractures
 ? Long term over suppression of bone? Long term over suppression of bone
turnover.turnover.
 Incidence : 1 in 10,000.Incidence : 1 in 10,000.
 Associated median treatment duration : 7Associated median treatment duration : 7
years.years.
 Causality : long term bp/ atypical #Causality : long term bp/ atypical #
unproven.unproven.
 Further large scale studies needed.Further large scale studies needed.

38. RecommendationsRecommendations
 Educate physician/patient aboutEducate physician/patient about
Prodromal pain.Prodromal pain.
 Evaluate with urgent X-Ray.Evaluate with urgent X-Ray.
 If negative, may consider MRI.If negative, may consider MRI.
 Stop BP’s if atypical fracture confirmed.Stop BP’s if atypical fracture confirmed.

39. Atrial fibrillationAtrial fibrillation
 FDA recommends physiciansFDA recommends physicians to not alterto not alter
their prescribing patterntheir prescribing patterns while it continuess while it continues
to monitor post marketing reports of AF into monitor post marketing reports of AF in
such patients.such patients.
 In v/o above and absence of definitiveIn v/o above and absence of definitive
data : Benefits of treatment outweigh risks.data : Benefits of treatment outweigh risks.

40. Esophageal cancerEsophageal cancer
 23 cases reported in last 223 cases reported in last 2
decades. (Wysowski et al)decades. (Wysowski et al)
 31 cases from31 cases from
Europe/Japan.Europe/Japan.
 Median time from use toMedian time from use to
diagnosis : 1-2 yr.diagnosis : 1-2 yr.
 Time from exposureTime from exposure
inconsistent w/ causalinconsistent w/ causal
relation.relation.
 Further studies neededFurther studies needed..

41. Renal safetyRenal safety
 Safe for creatinine clearance > 30 -35 mlSafe for creatinine clearance > 30 -35 ml/min./min.
 Lack of experience < 30 ml/min.Lack of experience < 30 ml/min.
 No data for use in ESRD.No data for use in ESRD.
 Exact bone disease unknown unless biopsy.Exact bone disease unknown unless biopsy.
 Expert opinion: half the dose could be usedExpert opinion: half the dose could be used
for 3 years in ESRD once bone biopsyfor 3 years in ESRD once bone biopsy
confirms osteoporosis.confirms osteoporosis.

42. Fracture
Bone
Strength
Material
Properties
Remodeling
Falls
Shape &
Architecture
Exercise &
Lifestyle
Hormones
Nutrition
Bone
Mass
Postural
Reflexes
Soft Tissue
Padding
Reproduced with permission from Heaney RP. Bone 33:457-465, 2003
Factors Leading to Osteoporotic Fracture:
Role of Bone Remodeling
2004

43. HIP FRACTURE – Female Age 75 and over
Give single oral dose 100,000 IU vitaminD @ as soon as feasible post hip fracture & start 1000mg
CaCO3+800IU vitaminD asap, (if on this already – continue)
Already on a BP(bisphosphonate)?
No
Yes
Good prognosis & eGFR 30 or over
Duration of treatment?Yes No
1. Patient or resident carer understand
concepts of osteoporosis, fracture risk
reduction & protocol for ingesting oral BP
AND
2. No contraindications to oral BPs
[dysphagia / oesophageal stricture /
achalasia /hypocalcaemia].
Yes
Oral ALN 70mg / wk
No
Patient suitable for IV BP
& eGFR 35 or over
Yes No
Arrange IV zoledronic acid 5mg
infusion (over at least 15min),
4-6/52 after hip fracture
Consider oral BP or, if at risk
equivalent to that of fracture
plus T-score -2.4 or less,
consider strontium ranelate.
Continue b.d. calcium + vitaminD
Continue b.d.
oral calcium + vitaminD
More than 2yr 2yr or less
Optimal compliance with / adherence
to BP & BP well tolerated
YesNo
Continue oral BP
IF eGFR is 30 or more
Otherwise continue
b.d. calcium + vitaminD
GREATER GLASGOW & CLYDE PROTOCOL FOR FRACTURE SECONDARY PREVENTION AFTER HIP FRACTURE IN WOMEN AGE 75+

44. Zoledronic acid 5 mg
IV once a year

46. Once Yearly Zoledronic AcidOnce Yearly Zoledronic Acid
Reduces FracturesReduces Fractures
HORIZON Pivotal Fracture Trial
Multi-national, multi-center, RCT
7,736 women age 65-89 with T-score <
-2.5 or fracture plus T-score < -1.5
Calcium 1000-1500 mg/day vit D (400-
1200 IU/day)
Zoledronic acid IV infusion 5 mg
lack et al. NEJM 356:1809-1822, 2007

47. ZOLZOL reducesreduces hiphip fracturefracture
*Relative risk reduction (95% confidence interval) vs placebo
Black et al. NEJM 356:1809-1822, 2007
P = .0024
1
2
3
0
Placebo (n = 3861)
ZOL 5 mg (n = 3875)
CumulativeIncidence(%)
Time to First Hip Fracture (months)
0 3 6 9 12 15 18 21 24 27 30 33 36
41%*
(17%, 58%)

48. P < .0001
CumulativeIncidence(%)
Time to First Clinical Vertebral Fracture (months)
0 3 6 9 12 15 18 21 24 27 30 33 36
77%
(63%, 86%)
Placebo (n = 3861)
ZOL 5 mg (n = 3875)
1
2
3
0
ZOLZOL reducesreduces vertebralvertebral
fxfx
*Relative risk reduction (95% confidence interval) vs placebo
Black et al. NEJM 356:1809-1822, 2007

49. P = .0002
Time to First Clinical Non-vertebral Fracture (months)
2
4
6
8
10
12
0 3 6 9 12 15 18 21 24 27 30 33 36
25%
(13%, 36%)
Placebo (n = 3861)
ZOL 5 mg (n = 3875)
0
CumulativeIncidence(%)
ZOLZOL reducesreduces non-vertebralnon-vertebral
fxfx
*Relative risk reduction (95% confidence interval) vs placebo
Black et al. NEJM 356:1809-1822, 2007

50. Zoledronic Acid will ImproveZoledronic Acid will Improve PatientPatient
Compliance asCompliance as Once-Yearly IV Therapy isOnce-Yearly IV Therapy is
PreferredPreferred
Data from Lindsay R, et al. Poster presented at ECCEO6; March 15-18, 2006; Vienna, Austria.
16.4
18.9
Both Are Equal
Once-Yearly IV
Once-Weekly Pill
More convenient
More willing to
take long term
Overall
preference
N = 122
66.4
59.8
0 20 40 60 80 100
68.0
66.4
15.6
18.0
20.5
15.6
19.7
13.9
% of Patients
More
satisfying

51. Take home pointsTake home points
 Osteoporosis :Osteoporosis : significant burden of diseasesignificant burden of disease..
 Main stay treatment :Main stay treatment : bisphosphonatesbisphosphonates..
 ? Duration of treatment : individualized.? Duration of treatment : individualized.
 Patient compliancePatient compliance
 Patient educationPatient education
  once yearly IV BPonce yearly IV BP
 More research needed to confirm associationMore research needed to confirm association
with ONJ, Sub trochanteric fracture.with ONJ, Sub trochanteric fracture.
 Benefits of treatmentBenefits of treatment outweigh risks inoutweigh risks in
osteoporosis.

52. Thank youThank you
Keep your bone healthyKeep your bone healthy