Dr. Atef A. Mahmoud, MD, FRCPProfessor of Internal Medicine & Rheumatology

Cairo Unversity

Management of Refractory cases of Osteoporosis

Case Study• F.M.A,84 years old Egyptian F., MRN

707962• Rheumatology OPD: (December 1977,

67yrs old)LBP, Hip and Knee pain lumbar spond., OA

• No H. of chronic medical diseaes, no fx. nor FH of fx.

December 1998 • BMD LS T – 1.5 FN T-1.5• Calcium 1000mg + Cholecalciferol 400 u/d

• June 2000 Graves disease , started on Neomercazol 30 mg/d controlled , dose reduced

• Hypertension , AF on coumadin INR 2.7• Dyslipidaemia on Atrovastatin 10 mg/dRepeat BMD, Auguest 2000 • Lumbar sp. T -1.65 FU -3.1% FN T -1.51 FU -3.7%• Start Alendronate Sodium 10 mg/d

Repeat BMD, January 2004• Osteopoenia , LS + 17.8% , FN + 15.8%• December 2006, still on Fosamax, no Fx.Repeat BMD in 2006 very satisfactory• Drug holiday for 2yrs. ,continue Cal. & vit. D

BMD repeated in january 2008 and March 2010 almost normal

March 2010

March 2010

Alendronate 70 mg Once Weekly is Therapeutically Equivalent to Alendronate 10 mg daily 11

FOSAMAX Increased Lumbar Spine BMD More Than Placebo

As seen in FLEX,

FLEX = FIT Long-term EXtension study; BMD = bone mineral density; FIT = Fracture Intervention TrialaPooled 5-mg and 10-mg groups; bError bars indicate 95% confidence interval; cMeasured in clinical fracture arm onlyAdapted from Black DM et al. JAMA. 2006;296:2927–2938.FOSAMAX (alendronate sodium) is a registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

FOSAMAX/FOSAMAXa FOSAMAX/placebo

0

2

4

12

14

16

0 1 2 3 4

BM

D C

hang

e Fr

om F

ITB

asel

ine,

Mea

n %

b

Year

FIT FLEX

6

8

10

0

2

4

12

14

16

0 1 2 3 4

Year

6

8

10

5

NumberFOSAMAX/FOSAMAX 648 648 647 645 449c 646 595 553FOSAMAX/placebo 431 429 430 426 293c 429 402 365

3.7%P<0.00

1

R

R

Urine NTxUrine NTxM

ean

Per

cent

Cha

nge

Month

Placebo*ALN 5 mgALN 10 mgALN 20 mg/ALN 5 mg/Placebo

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

0 12 24 36 48 60 72 84 96 108 120

*Patients enrolled in the original, 3 year study

Bone Turnover: Treatment Discontinuation

Urine NTx (Bone resorption)

Bone et al. N Engl J Med 2004; 350: 1189-1199

Alendronate 70 mg Once Weekly is Therapeutically Equivalent to Alendronate 10 mg daily 14

FOSAMAX Reduced the Incidence of Clinical Vertebral Fracture More Than Placebo

Frac

ture

Inci

denc

e, %

Clinical Vertebral Vertebral Morphometric Nonvertebral

As seen in FLEX,

0

Relative Risk Reduction=55%

RR=0.8695% CI (0.60, 1.22)

RR=1.0095% CI (0.76, 1.32)

5.3%

2.4%

11.3%9.8%

18.9% 19.0%

RR=0.4595% CI (0.24, 0.85)

5

10

15

20

25 FOSAMAX/FOSAMAX* (n=662)FOSAMAX/placebo (n=437)

FLEX = FIT Long-term EXtension study; RR = relative risk; CI=confidence interval*Pooled 5-mg and 10-mg groupsAdapted from Black DM et al. JAMA. 2006;296:2927–2938.FOSAMAX (alendronate sodium) is a registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

R

R

Alendronate 70 mg Once Weekly is Therapeutically Equivalent to Alendronate 10 mg daily 15

Alendronate 70 mg Once Weekly is Therapeutically Equivalent to Alendronate 10 mg daily 16

FDA Analysis: Duration of treatment , Bisphosphonates

Drug Core Study ,y

Extension Study, y

Alendronate 0-4 5-10Zoledronic

acid 0-3 4-6

Risedronate 0-3 4-5; 5-7

The FDA found no continued efficacy with long term (beyond 3-5 y) Bisphosphonate use.

Pooled data (n=2496) BPs 6+ years, Fx. rate 9.3-10.6%BPs/PBO, Fx. rate 8.0-8.8%

• Febuary 2011 Drainge of amaebic liver abscess

• September 2011 felt down from standing height

Fracture Rt. Humeral head

Fixation by plate & scews

Investigations

• Ser.Cr. 0.9 mg/dl , normal electrolyte• Hg 12.2 Plat. 142 WBC 14.8 N. 13.5• ESR 28• Cal.9.2 ALP 55 25OHD 68.7 nmol/L• Normal LFT• TSH 1.75 FT4 6.2 FT3 137 (on Neomecazol 5 mg/d)

• Started on Protelos 2gm/d + calcium & Vit.D on October 2011

• April 2012 felt down communated fx. of Lt. humerus

April 2012

• Protelos discontinued ( 6/12)

• Teriparatide (Forteo) 20 µg SC daily started

Auguest 2012

VFA

Auguest 2012

OPD April 2013 • Forteo (12/12) , no fractures, ambulatory• Calcium 500mg/d • Cholecalciferol 800 u/d• Thyroid study normal• Ser. Calcium ,Phosphorus, ALP, 25OHD

normal

March 2013

March 2013

Important Issues to Adress• Always check for secondary cause of bone

loss.• Duration of Bisphosphonate therapy• Drug holiday concept• Long term surveilance of osteoporotic

patients.• Falacies in BMD interpretation• Occurrence of fragility fractures with

normal BMD measurements

Bone Stiffness• Stiffness is the rigidity of an object — the

extent to which it resists deformation  in response to an applied force . 

• The complementary concept is flexibility or pliability: the more flexible an object is, the less stiff it is.

• The mineral gives bone its stiffness, without sufficient mineralization, bones will plastically deform under load

Bone Toughness

• Toughness : is the ability of the bone to absorb shock and is a measure of resistance to fracture

• Collagen provides toughness to bone making it less brittle so that it better resists fracture.

• Osteoid bone has toughness but not stiffness

37

Bone Mineralization

Mineral Content

Toughness

Hypomineralization Hypermineralization

Mineral = 64-66% of bone matrix weight

Dogs Treated with High Doses of Bisphosphonates

Mashiba T et al. J Bone Miner Res 15:613-620; 2000 *P<.05 vs placebo**P<.01 vs placebo

Mic

rocr

ack

Surf

ace

Den

sity

(m

/mm

2 )M

ean

± SE

M

Placebo

Risedronate

20

15

10

5

0

*

Alendronate

**

41

Hypermineralization of Bones

Easy Fractures ( Atypical )

Stiffness

Toughness

Why is Difficult to Define Non-Responders

• BMD changes account only partially to the anti-fracture effect of different therapies

• Need to wait 1-2 years to assess BMD response

• Therapies decrease but don’t eliminate fractures

• Medication compliance is generally low with therapies

Potential Causes of Poor Response

• The use of a weak anti-resorptive agent• Low bioavailability of the drug in the

subject• Low Ca and Vitamin D intake• Underlying secondary osteoporosis• Possible low bone turnover status

secondary to long term steroids use or chronic illness

• Incompliance to medications

Effect of Vit D Status on Response

Lumber Spine Femoral Neck0

1

2

3

4

5

6

Vitamin D Deplete Vitamin D Replete%

Cha

nge

in B

MD

The effect of cyclical Etidronate in women with low

BMD with Vit D depleted (<40

nmol/L)or repleted (>40 nmol/L)

Koster et al, Eur J Pharm, 1996,51:145

Definition of Non-responders

• In the FACT study Nonresponders were defined as having any measured BMD loss (from baseline) at two or more of the four measured sites at 24 months.

• Conversely Responders were defined as having either no change or any measured gain in BMD.

• In this study 85% of Alendronate patients and 62% of Residronate patients were responders after 24 months.

Definition of Non-responders (EUROFOROS)

1-Sustained at least one new vertebral or nonvertebral fragility fracture despite prior prescription of an AR therapy for at least 12 moths

2-Had a lumbar spine, total hip, or femoral neck BMD T-score of -3.0 or less after documented prior AR treatment for at least 24 moths; and/or

3-Experienced a decrease of >3.5% in BMD in 2 yr at any one of the skeletal sites measured, despite documented continuous prescription of an AR agent in the preceding 24 moths.

Investigations of Non-responders

Management of Poor Responders

• The use of other anti-osteoporosis agent• Optimal intake of Ca and Vitamin D• Treatment of underlying causes of secondary

osteoporosis ( 30% of PM women and 40% in osteoporotic men)

• Role of other new therapies and anabolic agents ?

Dr. Atef A. Mahmoud, MD, FRCPHead of Rheumatology & Rehabilitation Unit,

Dr. Erfan & Bagedo Hospital

Management of Refractory cases of Osteoporosis

Alendronate 70 mg Once Weekly is Therapeutically Equivalent to Alendronate 10 mg daily 58

Continuous Increases in Lumbar Spine BMD with Alendronate 10 mg over 10 Years

0 1 2 3 4 5 6 7 8 9 100

2

4

6

8

10

12

14

Year

Mea

n P

erce

nt C

hang

e (±

SE

)

ALN 5 mg (n=78)ALN 10 mg (n=86)ALN 20 mg/ALN 5 mg/Placebo (n=83)

Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

The mean percent change from baseline to year 10 appears in parentheses following each treatment group.

(9.3%) p<0.001

(13.7%) p<0.001

(9.3%) p<0.001

Alendronate 70 mg Once Weekly is Therapeutically Equivalent to Alendronate 10 mg daily 59

Sustained Increases in Total Hip BMD with Alendronate 10 mg over 10 Years

ALN 5 mg (n=78)ALN 10 mg (n=86)

ALN 20 mg/ALN 5 mg/Placebo (n=83)

Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

The mean percent change from baseline to year 10 appears in parentheses following each treatment group.

0 1 2 3 4 5 6 7 8 9 10

9

012345678

Year

Mea

n P

erce

nt C

hang

e (±

SE

)

(2.9%) p<0.05

(6.7%) p<0.001

(3.4%) p<0.001

Total Hip BMD Changes From FIT Baseline (mITT)

–1

0

1

2

3

4

5

0 12 24 36 48 60 72 84 96 108 120

Mea

n Pe

rcen

t Cha

nge

Month

P < 0.001 ALN/ALN vs ALN/PBO.

ALN/Placebo ALN/ALN (Pooled 5 mg and 10 mg groups)

Black et al JAMA 2006; 296: 2927-2938

FIT FLEX

2.57% (1.78-3.36)

61

Bone Composition: Stress & Strain

X

X

X

OsteoPetrosis Normal

OsteoMalacia

Strain

Stre

ss

Treating the high risk patient

Osteoporosis

Standard Treatment

“Failure” BMD and/or Turnover

Fracture

Escalate Treatment

Anabolic Rx (PTH)

High Risk Patient