1. Management of Refractory cases of Osteoporosis
Dr. Atef A. Mahmoud, MD, FRCP
Professor of Internal Medicine & Rheumatology
Cairo Unversity

2. 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 – FN T-1.5
Calcium 1000mg + Cholecalciferol 400 u/d

3. 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/d
Repeat BMD, Auguest 2000
Lumbar sp. T FU -3.1%
FN T FU -3.7%
Start Alendronate Sodium 10 mg/d

4. Repeat BMD, January 2004
Osteopoenia , LS % , FN %
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

5. January 2008

6. January 2008

7. January 2008

8. March 2010

9. March 2010

10. March 2010

11. FOSAMAX Increased Lumbar Spine BMD More Than Placebo
As seen in FLEX,
FOSAMAX Increased Lumbar Spine BMD More Than Placebo R
Ref 1, p 2928, C2, L1-8, ¶1, L18-21, C3, ¶1, L1-7; p 2932, Fig 2, Caption, L1-3, Table 2, Row 4, Footnote, L4
FOSAMAX/FOSAMAXa FOSAMAX/placebo 16
FIT 16
FLEX 14 14
3.7%
P<0.001 12 12 10 10
BMD Change From FIT Baseline, Mean %b 8 8 6 6 4 4
Ref 1, p 2932, Table 2, Row 4, Footnote, L4, Fig 2; p 2933, C2, L4-9 2 2
As shown above, 5 additional years of treatment with FOSAMAX™ was associated with an increase of 5.26% in bone mineral density (BMD) at the lumbar spine, while treatment with placebo was associated with an increase of 1.52%. The difference between groups was significant at P< This means that women who remained on FOSAMAX increased lumbar spine BMD by 14.8% from Fracture Intervention Trial (FIT) baseline.1 1 2 3 4 1 2 3 4 5
Year
Year
Number
FOSAMAX/FOSAMAX c
FOSAMAX/placebo c
FLEX = FIT Long-term EXtension study; BMD = bone mineral density; FIT = Fracture Intervention Trial
aPooled 5-mg and 10-mg groups; bError bars indicate 95% confidence interval; cMeasured in clinical fracture arm only
Adapted 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
FOSAMAX™ (alendronate) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Reference
1. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA.  2006;296:2927–2938.

12. FOSAMAX Increased Hip Trochanter BMD More Than Placebo
As seen in FLEX,
FOSAMAX Increased Hip Trochanter BMD More Than Placebo R
Ref 1, p 2928, C2, L1-8, ¶1, L18-21, C3, ¶1, L1-7; p 2932, Fig 2, Table 2, Row 3, Footnote, L4
FOSAMAX/FOSAMAXa FOSAMAX/placebo 16
FIT 16
FLEX 14 14 12 12 10 10
BMD Change From FIT Baseline, Mean %b 8 8
Five additional years of treatment with FOSAMAX™ was associated with a nonsignificant increase in bone mineral density (BMD) at the hip trochanter, whereas treatment with placebo was associated with significantly decreased hip trochanter BMD (P<0.001). The mean percentage change during the Fracture Intervention Trial (FIT) Long-term EXtension (FLEX) study was –0.08% among the pooled women given FOSAMAX/FOSAMAX and –3.25% among those given FOSAMAX/placebo. The difference in the mean percent change between the group given FOSAMAX/FOSAMAX and that given FOSAMAX/placebo was 3.2% (95% confidence interval: 2.49, 3.84; P<0.001).1 6 6
3.2%
P<0.001 4 4
Ref 1, p 2932, Table 2, Row 3, Footnote, L4, Fig 2 2 2 1 2 3 4 1 2 3 4 5
Year
Year
Number
FOSAMAX/FOSAMAX c
FOSAMAX/placebo c
FLEX = FIT Long-term EXtension study; BMD = bone mineral density; FIT = Fracture Intervention Trial
aPooled 5-mg and 10-mg groups; bError bars indicate 95% confidence interval; cMeasured in clinical fracture arm only
Adapted 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
FOSAMAX™ (alendronate) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Reference
1. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA.  2006;296:2927–2938.

13. Bone Turnover: Treatment Discontinuation
Bone Turnover: Treatment Discontinuation
Urine NTx (Bone resorption)
Bone et al. N Engl J Med 2004; 350:

14. Relative Risk Reduction=55%
As seen in FLEX,
FOSAMAX Reduced the Incidence of Clinical Vertebral Fracture More Than Placebo R
Ref 1, p 2934, Table 3, L1,2,4 + n values + calc
Calc: 1.0–0.45100=55% 25
FOSAMAX/FOSAMAX* (n=662)
FOSAMAX/placebo (n=437) 20
18.9%
19.0%
Relative Risk Reduction=55% 15
Fracture Incidence, %
11.3%
The incidence of fractures was an exploratory endpoint of the Fracture Intervention Trial (FIT) Long-term EXtension (FLEX) study.1 Data for the 2 dosage levels of FOSAMAX™ were pooled.
Patients who continued on FOSAMAX were less likely to have a clinical vertebral fracture; there was a 2.4% incidence among patients on active treatment, compared with 5.3% among patients taking placebo. This is a relative risk reduction of 55%.1
The morphometrically detected vertebral fracture rate of 9.8% among women given FOSAMAX was not significantly lower than the rate seen among patients taking placebo—11.3%. Rates of nonvertebral clinical fracture were similar for both groups as well—18.9% and 19.0%, respectively.1
9.8% 10
Ref 1, p 2930, C1, ¶2, L1-3; p 2934, Fig 4, legend
Ref 1, p 2934, C1, ¶1, L calc
Calc: 1.0–0.45100=55%
Ref 1, p 2934, C1, ¶1, L1-6,12, C2, L1-6
5.3% 5
2.4%
Clinical Vertebral
Vertebral Morphometric
Nonvertebral
RR=0.45
95% CI (0.24, 0.85)
RR=0.86
95% CI (0.60, 1.22)
RR=1.00
95% CI (0.76, 1.32)
FLEX = FIT Long-term EXtension study; RR = relative risk; CI=confidence interval
*Pooled 5-mg and 10-mg groups
Adapted 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
FOSAMAX™ (alendronate) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Reference
1. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA.  2006;296:2927–2938.

16. FDA Analysis: Duration of treatment , Bisphosphonates
Drug
Core Study ,y
Extension Study, y
Alendronate
0-4
5-10
Zoledronic acid
0-3
4-6
Risedronate
4-5; 5-7
Pooled data (n=2496) BPs 6+ years, Fx. rate %
BPs/PBO, Fx. rate %
The FDA found no continued efficacy with long term (beyond 3-5 y) Bisphosphonate use.

17. Febuary 2011  Drainge of amaebic liver abscess
September 2011  felt down from standing height

18. Fracture Rt. Humeral head

19. Fixation by plate & scews

20. Investigations
Ser.Cr. 0.9 mg/dl , normal electrolyte
Hg Plat WBC N. 13.5
ESR 28
Cal ALP OHD nmol/L
Normal LFT
TSH FT FT3 137
(on Neomecazol 5 mg/d)

21. Started on Protelos 2gm/d + calcium & Vit.D on October 2011
April 2012  felt down  communated fx. of Lt. humerus

22. April 2012

23. Protelos discontinued ( 6/12)
Teriparatide (Forteo) 20 µg SC daily started

24. Auguest 2012

25. Auguest 2012

27. VFA

28. Auguest 2012

30. 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

31. March 2013

32. March 2013

33. 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

34. 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

35. 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

36. Bone Toughness: Type 1 Collagen
Small influence on bone strength and stiffness
Improves bone toughness
Main protein building block in bone

37. Bone Mineralization Mineral Content
Mineral = 64-66% of bone matrix weight
Toughness
Hypomineralization
Hypermineralization
Mineral Content

38. Resorption Removing a Microcrack
Burr 2001

39. Dogs Treated with High Doses of Bisphosphonates20 ** * 15
Microcrack Surface Density (m/mm2)
Mean ± SEM 10
This study evaluated the effect of bisphosphonate induced reduction in bone turnover on microdamage accumulation and biomechanical properties of cortical bone.
1-2 year old female beagles were treated for 12 months with either risedronate (0.5 mg/kg/d) or alendronate (1.0 mg/kg/d).
The doses of bisphosphonates used in this study were 5 to 7 times higher than that used in humans for osteoprorosis treatment.
Significant suppression of cortical remodeling was observed (RIS 53% and ALN 68%), and there was a significant increase in microdamage accumulation (RIS 155% and ALN 322%), compared to placebo treated animals.
Alendronate treatment also significantly reduced bone toughness by 20%, compared to placebo. 5
Placebo
Risedronate
Alendronate
*P<.05 vs placebo
**P<.01 vs placebo
Mashiba T et al. J Bone Miner Res 15: ; 2000

40. 1-2 year old female beagles were treated for 12 months with either risedronate (0.5 mg/kg/d) or alendronate (1.0 mg/kg/d).
The doses of bisphosphonates used in this study were 5 to 7 times higher than that used in humans for osteoprorosis treatment.
Significant suppression of cortical remodeling was observed (RIS 53% and ALN 68%), and there was a significant increase in microdamage accumulation (RIS 155% and ALN 322%), compared to placebo treated animals.
Alendronate treatment also significantly reduced bone toughness by 20%, compared to placebo.
Mashiba T et al. J Bone Miner Res 15: ; 2000

41. Hypermineralization of Bones Easy Fractures ( Atypical )
Stiffness
Toughness
Easy Fractures ( Atypical )

42. NON RESPONDERS

43. 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

44. 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

45. Effect of Vit D Status on Response
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

46. Secondary Causes in Men Presenting With Vertebral Fx

47. Secondary Causes in Women Presenting With Vertebral Fx

48. Compliance Issues Within 6 mo 14.3 9.1 9.8 5.9 11.8 6-12 mo 5.4 5.3
Ca and VtD
Raloxifen
Alend Daily
Alend
weekly
Resid Daily
Within 6 mo
14.3
9.1
9.8
5.9
11.8
6-12 mo
5.4
5.3
6.6
0.9
4.7
>12 mo
2.9
1.9
4.5
0.1
2.5
Total
22.7
16.3
20.9
6.9 19

49. Low compliance leads to low efficacy
Protective effect of bisphosphonates ( patients)
starts >50 % compliance
optimal >80% compliance
In this study  1/2 patients <80% compliance !
Fracture risk at 24 months
Compliance to bisphosphonates (MPR)
50%
Below efficacy zone
80%
Siris ES,. Mayo Clin Proc Aug;81(8):

50. 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.

51. 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.

52. Baseline Factors Predicting Poor Response

53. Baseline Factors Predicting Poor Response

54. Investigations of Non-responders

55. 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 ?

56. Thank You
Dr.Atef Mahmoud 56

57. Management of Refractory cases of Osteoporosis
Dr. Atef A. Mahmoud, MD, FRCP
Head of Rheumatology & Rehabilitation Unit,
Dr. Erfan & Bagedo Hospital 57

58. Mean Percent Change (±SE)
Continuous Increases in Lumbar Spine BMD with Alendronate 10 mg over 10 Years 2 4 6 8 10 12 14
(13.7%) p<0.001
(9.3%) p<0.001
(9.3%) p<0.001
Mean Percent Change (±SE)
ALN 5 mg (n=78)
BMD at the lumbar spine continued to increase during years 6 through 10 and 8 through 10 in both alendronate 5 mg and 10 mg groups. The mean cumulative increase after 10 years of the 10 mg daily dose was 13.7% (p<0.001), as compared with the baseline value; smaller gains occurred in the 5 mg group.4
In the discontinuation group (ALN 20/5/PBO), BMD at the lumbar spine did not change significantly after year 5.4
ALN 10 mg (n=86)
ALN 20 mg/ALN 5 mg/Placebo (n=83) 1 2 3 4 5 6 7 8 9 10
Year
The mean percent change from baseline to year 10 appears in parentheses following each treatment group.
Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

59. Mean Percent Change (±SE)
Sustained Increases in Total Hip BMD with Alendronate 10 mg over 10 Years 9 1 2 3 4 5 6 7 8
ALN 5 mg (n=78)
ALN 20 mg/ALN 5 mg/Placebo (n=83)
ALN 10 mg (n=86)
(6.7%) p<0.001
Mean Percent Change (±SE)
(3.4%) p<0.001
Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 6.7% at the total hip as compared with baseline values (p<0.001). Smaller gains occurred in the group given 5 mg daily (p<0.05). In the discontinuation group (ALN 20/5/PBO), BMD significantly decreased but remained above baseline values (p<0.001).4
(2.9%) p<0.05 1 2 3 4 5 6 7 8 9 10
Year
The mean percent change from baseline to year 10 appears in parentheses following each treatment group.
Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

60. Total Hip BMD Changes From FIT Baseline (mITT)
ALN/Placebo ALN/ALN (Pooled 5 mg and 10 mg groups)
P < ALN/ALN vs ALN/PBO. 5 4 3
Mean Percent Change 2
2.57%
( ) 1
FIT FLEX –1 12 24 36 48 60 72 84 96
108
120
Month
Black et al JAMA 2006; 296:

61. Bone Composition: Stress & Strain
Normal X
OsteoPetrosis X
Stress
OsteoMalacia
Stress= load per unit area
Strain = fractional or % change in Length
Osteomalacia= osteo (bone) ‘malacia’ (softness) = soft bone = bone is poorly mineralized and weak but very ductile. Bone may undergo large deformation without breaking.
Osteopetrosis= bone is very stiff, but also very brittle X
Strain

62. Treating the high risk patient
Osteoporosis
Standard Treatment
“Failure”
BMD and/or  Turnover
Fracture
High Risk
Patient
Escalate
Treatment
Anabolic Rx
(PTH)