1. CHAPTER II Osteoporosis: treatments

2. La Lettre du Rhumatologue Results of the FREEDOM study (open-label) at 5 years ● Effects of denosumab : BMD evaluation at 5 years ● After 3 years of treatment : 2 343 " long term " group 2 207 " de novo " group  BMD increase continues at 5 years of treatment  Tolerance: no ONJ or atypical fractures in the " long term " group ; 2 ONJ cases in the « de novo » group Incidence of new NVF BL12345 1234 5 Treatment duration (years) 0 2 4 6 8 10 12 14 -2 0 2 4 6 8 Lumbar BMDTotal hip BMD BMD variation (%, CI 95 ) DenosumabPlacebo * * * * * * * * * * * * *p < 0,002 versus placebo and baseline values 12345 0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 Yearly incidence of nonvertebral fractures (%) 3,1 2,6 2,7 2,0 2,3 1,9 1,2 1,1 FREEDOMExtension study PlaceboDenosumab Variation de la DMO (%, IC 95 ) Yearss ASBMR 2010 - D’après Papapoulos (1025) 20 Osteoporosis: treatments

3. La Lettre du Rhumatologue ASBMR 2010 - D’après Jamal S et al., Toronto, Canada, abstr. 1068, actualisé Denosumab : different efficacy by level of renal function ? ● Stratification in 4 subgroups according to creatinine clearance  Antifracture efficacity of denosumab is comparable with respect to renal function  No differences in incidence of adverse events BMD variation (%) 15-29 ml/mn (n = 73) 30-59 ml/mn (n = 2 817) 60-89 ml/mn (n = 4 069) > 90 ml/mn (n = 842) Lumbar 5.0 (-0.8-10.8) 8.9 (8.4-9.3) 9.0 (8.6-9.4) 8.1 (7.2-8.9) Femoral neck 5.9 (3.3-8.5) 5.1 (4.7-5.5) 5.2 (4.9-5.5) 5.6 (4.9-6.3) Total hip 5.9 (3.0-8.7) 6.4 (6.1-6.7) 6.4 (6.2-6.7) 5.8 (5.2-6.3) N1 3 6913 70233311 3091 3321 9621 924394413 All patients 15-29 ml/mn 30-59 ml/mn 60-89 ml/mn > 90 ml/mn 0 1 2 3 4 5 6 7 8 9 10 7.2 2.3 9.1 3.2 7.0 2.9 7.0 1.8 8.1 3.1 Placebo (n = 3 906)Denosumab (n = 3 902) Incidence of vertebral fractures (3 years, (%) BMD Variation within the 4 groups over 3 years * * * * 21 Osteoporosis: treatments *p < 0.05 Incidence of vertebral fractures

4. La Lettre du Rhumatologue ● Design: at the end of 3 years of the HORIZON study, female patients treated with zoledronic acid were randomly assigned to 2 groups : placebo (Z6 : n = 616) or continuation of treatment (Z3P3 : n = 617) ● Résultats –Difference of femoral BMD between the Z6 group and the Z3P3 placebo group = 1 % –No difference between the 2 groups for clinical fractures –Reduction of 52 % in the number of radiologic vertebral fractures (n = 14 versus n = 30) within the Z6/Z3P3 group  Zoledronic acid long-term treatment does not expose to an increased risk of side effects  The question of the interest of prolonged treatment remains open 34,56 0 -0,5 -1,5 0,5 2,5 2 1,5 1 Z6 Z3P3 Ans Evolution (%) 1 % p < 0,001 Femoral neck BMD 0 5 10 15 Initial study (0-3 years) Z3P3 Éxtension study (3-6 years) Z6 PBO 10,9 % ZOL 3,3 % 6,2 % (20/486) 3,0 % (14/469) RR = 0,48 IC 95 (0,3 -0,9) p = 0,03 Reduction : -52 % New radiological vertebral fractures Female patients (%) HORIZON study 6-year extension ASBMR 2010 - D’après Black (1070) 22 Osteoporosis: treatments

5. La Lettre du Rhumatologue ASBMR 2010 - D’après Black D et al., San Francisco, États-Unis, abstr. 1028, actualisé What is the efficacy of a single injection of zoledronic acid ? ● Post hoc analysis of antifracture efficacy after 3 years in patients having received a single injection of zoledronic acid  A single injection induces a reduction of 32 % of the risk of new fractures at 3 years  The number of ‘lost to follow-up’ is significant in this group 0102030 0 5 10 15 20 0102030 0 5 10 15 20 Zoledronic acid Placebo p = 0.0389 p < 0.0001 1 3678583682946 904 6 662n = 1 single perfusion (n = 1 367) 3 perfusions (n = 6 904) Follow-up duration : 3 years Type of fracture 1 perfusion (n = 1 367) 3 perfusions (n = 6 904) n frac. Reduction (%)p n frac. Reduction (%)p All fractures 10532 %0.0446634 %< 0.0001 Clinical vertebral fractures 1456 % 0.12 (NS) 6466 %< 0.0001 Nonvertebr al fractures 9324 % 0.16 (NS) 41427 %< 0.0001 Cumulated events (%) RR : 0.68p = 0.04 Follow-up duration: 3 years RR : 0.66p < 0.0001 23 Osteoporosis: treatments Cumulated events (%) Months

6. La Lettre du Rhumatologue  Disintegration rate of alendronate generic versions is superior to the disintegration rate of alendronate, which raises tolerability and efficacy issues Disintégration median (in seconds) Comparison of disintegration rates Novo-alendronate 70 mg Apo-alendronate 70 mg Actonel ® 35 mg Fosamax ® 70 mg Fosavance ® 70 mg 0 50 100 150 200 250 300 350 400 450 500 Bisphosphonate generics : a rapid disintegration ASBMR 2010 - D’après Olszynski (FR0390) 24 Osteoporosis: treatments

7. La Lettre du Rhumatologue Diagnostic criteria for atypical femoral fracture ● Major criteria –Fracture line in a proximal site should be under the lesser trochanter and, in distal site, over the femoral condyles –It should be a nontraumatic fracture, or following a low-energy trauma –Fracture line should be transversal or oblique, with a < 30° angle –It should be a noncomminuted fracture –Complete fractures involve the entire crossection of the bone, from one cortical to the other, with a possible internal « thorn » –Incomplete fractures affect only the external cortical  Exclusion criteria: femoral neck fractures, intertrochanteric fractures with a subtrochanteric extension, periprosthetic or pathological fractures within the context of primary bone tumors or bone metastasis  All major criteria are required for diagnosis  The minor criteria are not necessary (for diagnosis) but sometimes (we) come across their association  Minor criteria –Periosteal reaction on the external cortical –Increase of cortical thickness –Dull pain prodromes in thigh s and inner thighs –Bilateral fracture –Delayed cicatrization –Associated comorbidities : rheumatoid arthritis, vitamin D insufficiency, hypophosphatasia… –Associated therapies : bisphosphonates, corticoids, proton pump inhibitors … Medial spine Short-oblique configuration Noncomminuted ASBMR 2010 – Task Force concernant les fractures fémorales atypiques (16 octobre 2010) 25 Osteoporosis: treatments

8. La Lettre du Rhumatologue Is the incidence of subtrochanteric fractures increasing? ● National data base (United States) on hip fractures between 1996 and 2007 coupled with a data base on the use of bisphosphonates  Hospitalizations for subtrochanteric fractures are rare, but they are increasing in menopausal women.  The number of menopausal patients under bisphosphonate treatment has been increasing during the same period.  But, at the same time, the number of classic hip fractures is decreasing. 1995 0 1998 2000 2002 2004 2008 1995 1998 2000 2002 2004 2008 15 20 25 30 35 40 200 400 600 800 1 000 1 200 Incidence Incidence (%) Women Men Women Men Subtrochanteric fracturesHip fractures ASBMR 2010 - D’après Wang (1029) 26 Osteoporosis: treatments

9. La Lettre du Rhumatologue  For these atypical femoral fractures, ● no association with alendronate in the New Zealand study ● an apparent association between BP and atypical fractures in the Australian study, but with a very weak frequency of the latter ● treatment benefits prevail over potential risk ● 2 retrospective monocenter 5-year studies : radiographic analysis New Zealand study : 71 subtrochanteric and diaphyseal fractures, of which 11 atypical fractures Alendronate median duration not specified All BP : RR = 2.1 (0.5-8.2), p = 0.16 Australian study : 152 subtrochanteric and diaphyseal fractures, of which 20 atypical fractures Alendronate median duration 5.1 years All BP : RR = 37.4 (12.9-119), p < 0.001 Atypical (11)Typical (60) Age (years)81 (66-96)81 (44-100) Men/Women1/1011/49 Alendronate48 Etidronate05 Calcium618 Vitamin D614 Glucocorticoïds25 IPP04 Fracture background628 TotalDiaphyseSubtrochanterDistal Atypical201550 Typical132156552 Bisphosphonates Alendronate (median duration) Risedronate (median duration) Atypical (n = 20) 17 (85 %) 15 (5.1 ans) 2 (3 ans) Typical (n = 132) 3 (2.3 %)2 (3.5 ans)1 (1 an) ASBMR 2010 - D’après Warren (1030) et Girgis (1071) 27 Osteoporosis: treatments Are patients who received long acting bisphosphonates at risk for atypical fractures ?

10. La Lettre du Rhumatologue What is the incidence of subtrochanteric and diaphyseal fractures before and after treatment against osteoporosis ? ● National Danish registry, matched-centrals study ● Each user of an antiosteoporosis treatment between 1996 and 2006 (n = 103 562) was matched, after adjustment for age and sex, with 3 controls (n = 310 683)  There was an increased risk for subtrochanteric and diaphyseal fractures before starting the treatment against osteoporosis. This increased risk was especially high in the year preceding start of treatment.  With alendronate, such increased risk diminishes progressively with treatment. Alendronate Clodronate Étidronate Ibandronate Pamidronate PTH Raloxifene Risedronate Strontium Zoledronate 0 4 8 12 16 20 IRR (IC 95 ) 0 1 2 3 4 5 6 7 > 10 years 5-10 yearss 1-5 years < 1yearn < 1 year 1-5 years > 5 yearss Before and after periods IRR (IC 95 ) Before After Subtrochanteric fractures and alendronate ASBMR 2010 - D’après Vestergaard (1072) 28 Osteoporosis: treatments

11. La Lettre du Rhumatologue ASBMR 2010 - D’après Kelly (FR0355) Incidence of subtrochanteric fractures in the SOF cohort ● 1 396 hip fractures, 45 of which were subtrochanteric fractures  Subtrochanteric fractures represent less than 2 % of hip fractures  The incidence of subtrochanteric fractures increases with patient age, with a same pattern as for hip fractures Femoral → 58,1/10 000 Intertrochanteric → 49,1/10 000 Subtrochanteric → 3,1/10 000 0 50 100 150 65-6970-7475-7980-8485+ Age (years) Incidence for 10 000 persons-year 29 Osteoporosis: treatments

12. La Lettre du Rhumatologue Breast cancer risk is reduced with alendronate ● Cohort study from a Danish national registry ● Women > 50 years,without cancer history that have been treated with alendronate from 1996 to 2005 –30 606 users –4 centrals matched for to age and sex (n = 122 424)  This national registry, based on a cohort study, shows a significant reduction of the risk of developping and dying from breast cancer in postmenopausal women treated with alendronate 0 1 2 3 Combined Incidence (%) 02468 Years Controls Alendronate Diagnostic of breast cancer RR = 0.74 (0.66-0.84) ; p < 0.001 Death due to breast cancer RR = 0,52 (0,40-0,68) ; p < 0,001 ASBMR 2010 - D’après Abrahamsen (SU0128) 30 Osteoporosis: treatments

13. La Lettre du Rhumatologue Comparison of transdermal and subcutaneous pharmacokinetic and pharmacodynamic profiles  Transdermal teriparatide has a pharmacokinetic and a pharmacodynamic profile on the bone remodeling markers comparable to subcutaneous teriparatide 20  g profile. Variations of bone remodeling markers PTH mean value (pg/ml) Hours Variations (%) ASBMR 2010 - D’après Kenan Y et al., Lod, Israël, abstr. FR0376, actualisé 012345678 0 50 100 150 200 SC20 TD50 TD80 04872960487296 0 50 100 150 200 250 300 0 50 100 150 200 250 300 PINPCTX Days 31 Osteoporosis: treatments Effect of transdermal teriparatide on bone remodeling *B *A * *B *A * * * * * * * * * * * *p < 0,05 versus baseline ; A p< 0,05 TD50 versus TD80 ; B p < 0,01 SC20 versus TD80

14. La Lettre du Rhumatologue ASBMR 2010 - D’après Gee AH et al., Cambridge, Royaume-Uni, abstr. 1250, actualisé What is the impact of teriparatide on the cortical bone of women with osteoporosis? ● In vivo study using High Resolution Cortical Thickness mapping ● 65 women (median age: 67.5 years) from the EUROFORS study, treated with teriparatide for 2 years  At 24 months teriparatide increases the cortical thickness of ● Tension zones involved in walking (muscle insertion sites) ● Upper part of the cortical, critical zone for the susceptibility to hip fracture risk Mapping and significance of cortical thickness modifications (besides the femoral head) 24 months - baseline Thickness variations (%) -202468 0,050,025 0 p for topographic distribution (a) p = 0,00000004 (b) p = 0,00007 (c) p = 0,00007 32 Osteoporosis: treatments

15. La Lettre du Rhumatologue Are the vibrations beneficial for bone ? ● Randomized, placebo controlled, ITT trial, with evaluation on the BMD at 12 months ● 202 menopausal women with osteopenia and controls (n = 67) ● Vertical acceleration : 0.3 g (90 Hz [n = 67], 30 Hz [n = 68]) ● Similar demographic parameters (age, menopause duration, weight, BMI, ethnics)  Beneficial effect in ITT vibrations on BMD has not been demonstrated  Lack of data on muscle evaluation, weight at one year, quality of life, etc. Densitometry data characteristics, vitaminD-calcium contribution Initial caracteristicsType90 Hz30 HzWitnesses Mean BMD (g/cm -2 ),(SD)Femoral neck0.686 (0,049)0.676 (0,060)0.687 (0.054) Total hip0.851 (0,066)0.836 (0,083)0.845 (0.068) Lumbar spince0.904 (0,090)0.890 (0,069)0.902 (0.080) Mean vBMD (mg:cm -3 ), (SD)Trabecular tibial bone149 (36)144 (29)145 (30) Calcium (mg), mean + ET (SD)Total1 538 (677)1 399 (656)1 352 (642) Vitamin D (UI), mean+ ET (SD)Total866 (582)778 (583)808 (584) Phisycal activity (kcal/j), mean (SD)Metabolic index352 (224)337 (237)383 (227) ASBMR 2010 - D’après Slatkovska (1027) 33 Osteoporosis: treatments

16. La Lettre du Rhumatologue ASBMR 2010 - D’après Jamal S et al., Toronto, Canada, abstr. 1252, actualisé  NTG seems to have beneficial effects on bone remodeling and BMD at 24 months BMD variations at 24 months Markers variations at 12 months 34 Osteoporosis: treatments An explosive treatment… nitroglycerin (NTG) !