CHAPTER II Osteoporosis treatments Osteoporosis treatments 20 Results

CHAPTER II Osteoporosis: treatments

Osteoporosis: treatments 20 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 Incidence of new NVF 14 12 10 8 6 4 2 0 * * * BL 1 2 3 4 Treatment duration (years) Denosumab 5 8 6 * * 4 * * 2 0 -2 BL 1 2 3 4 Treatment duration (years) Placebo FREEDOM 3, 5 Total hip BMD 5 Yearly incidence of nonvertebral fractures (%) BMD variation (%, CI 95) Lumbar BMD Variation de la DMO (%, IC 95) 2 207 "de novo" group 3, 0 Extension study 3, 1 2, 6 2, 7 2, 3 2, 5 2, 0 1, 9 2, 0 1, 5 1, 2 1, 1 1, 0 0, 5 0, 0 1 *p < 0, 002 versus placebo and baseline values 2 Placebo 3 4 5 Yearss Denosumab è BMD increase continues at 5 years of treatment è Tolerance: no ONJ or atypical fractures in the"long term" group; 2 ONJ cases in the « de novo » group La Lettre du Rhumatologue ASBMR 2010 - D’après Papapoulos (1025)

Osteoporosis: treatments 21 Denosumab : different efficacy by level of renal function ? ● Stratification in 4 subgroups according to creatinine clearance 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) 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) Lumbar Incidence of vertebral fractures (3 years, (%) BMD Variation within the 4 groups over 3 years Placebo (n = 3 906) Denosumab (n = 3 902) 10 *p < 0. 05 9. 1 9 8 7. 2 7. 0 7 6 5 * * 4 3. 2 2. 9 2. 3 3 * 1. 8 2 1 0 1 309 1 332 1 962 1 924 N 1 3 691 3 702 33 31 All patients 15 -29 ml/mn 30 -59 ml/mn 60 -89 ml/mn 8. 1 * 3. 1 394 413 > 90 ml/mn è Antifracture efficacity of denosumab is comparable with respect to renal function è No differences in incidence of adverse events La Lettre du Rhumatologue ASBMR 2010 - D’après Jamal S et al. , Toronto, Canada, abstr. 1068, actualisé

Osteoporosis: treatments 22 HORIZON study 6 -year extension ● Design: at the end of 3 years of the HORIZON study, female patients treated with zoledronic acid were randomly assigned to 2 groups : placebo (Z 6 : n = 616) or continuation of treatment (Z 3 P 3 : n = 617) New radiological vertebral fractures 15 2, 5 2 1, 5 1 0, 5 0 -0, 5 -1 -1, 5 Z 6 Z 3 P 3 ● Résultats 4, 5 6 Ans RR = 0, 48 IC 95 (0, 3 -0, 9) p = 0, 03 PBO 10, 9 % 10 5 0 3 – – – 1 % p < 0, 001 Female patients (%) Evolution (%) Femoral neck BMD 6, 2 % (20/486) ZOL 3, 3 % Initial study (0 -3 years) Z 3 P 3 Reduction : -52 % 3, 0 % (14/469) Éxtension study (3 -6 years) Z 6 Difference of femoral BMD between the Z 6 group and the Z 3 P 3 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 Z 6/Z 3 P 3 group è Zoledronic acid long-term treatment does not expose to an increased risk of side effects è The question of the interest of prolonged treatment remains open La Lettre du Rhumatologue ASBMR 2010 - D’après Black (1070)

Osteoporosis: treatments 23 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 1 single perfusion (n = 1 367) 3 perfusions (n = 6 904) Zoledronic acid Cumulated events (%) Placebo 20 15 10 5 p = 0. 0389 0 0 n = 1 367 Follow-up duration : 3 years 10 858 20 368 RR : 0. 68 30 294 p = 0. 04 Months Type of fracture 20 15 p < 0. 0001 0 0 6 904 Follow-up duration: 3 years 10 20 30 6 904 6 662 RR : 0. 66 p < 0. 0001 3 perfusions (n = 6 904) n frac. Reduction (%) p All fractures 105 32 % 0. 04 466 34 % < 0. 0001 Clinical vertebral fractures 14 56 % 0. 12 (NS) 64 66 % < 0. 0001 Nonvertebr al fractures 93 24 % 0. 16 (NS) 414 27 % < 0. 0001 10 5 1 perfusion (n = 1 367) è A single injection induces a reduction of 32 % of the risk of new fractures at 3 years è The number of ‘lost to follow-up’ is significant in this group La Lettre du Rhumatologue ASBMR 2010 - D’après Black D et al. , San Francisco, États-Unis, abstr. 1028, actualisé

Osteoporosis: treatments 24 Bisphonate generics : a rapid disintegration Comparison of disintegration rates Disintégration median (in seconds) 500 450 400 350 300 250 200 150 100 50 0 Novo-alendronate 70 mg Apo-alendronate 70 mg Actonel® 35 mg Fosamax® 70 mg Fosavance® 70 mg è Disintegration rate of alendronate generic versions is superior to the disintegration rate of alendronate, which raises tolerability and efficacy issues La Lettre du Rhumatologue ASBMR 2010 - D’après Olszynski (FR 0390)

Osteoporosis: treatments 25 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 Short-oblique configuration Medial spine · 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 : bisphonates, corticoids, proton pump inhibitors … Noncomminuted è Exclusion criteria: femoral neck fractures, intertrochanteric fractures with a subtrochanteric extension, è è 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 La Lettre du Rhumatologue ASBMR 2010 – Task Force concernant les fractures fémorales atypiques (16 octobre 2010)

Osteoporosis: treatments 26 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 bisphonates Subtrochanteric fractures Hip fractures 1 200 40 Women 30 25 20 Men 15 0 1995 1998 2000 Women 1 000 Incidence (%) 35 2002 800 600 Men 400 2004 2008 200 1995 1998 2000 2002 2004 2008 è Hospitalizations for subtrochanteric fractures are rare, but they are increasing in menopausal women. è The number of menopausal patients under bisphonate treatment has been increasing during the same period. è But, at the same time, the number of classic hip fractures is decreasing. La Lettre du Rhumatologue ASBMR 2010 - D’après Wang (1029)

Osteoporosis: treatments 27 Are patients who received long acting bisphonates at risk for atypical fractures ? ● 2 retrospective monocenter 5 -year studies : radiographic analysis New Zealand study : 71 subtrochanteric and diaphyseal fractures, of which 11 atypical fractures Atypical (11) Typical (60) Age (years) 81 (66 -96) 81 (44 -100) Men/Women 1/10 11/49 Alendronate 4 8 Etidronate 0 5 Calcium 6 18 Vitamin D 6 14 Glucocorticoïds 2 5 IPP 0 4 Fracture background 6 28 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 Total Diaphyse Subtrochanter Distal Atypical 20 15 5 0 Typical 132 15 65 52 Bisphonates 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) Alendronate median duration 5. 1 years All BP : RR = 37. 4 (12. 9 -119), p < 0. 001 è 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 La Lettre du Rhumatologue ASBMR 2010 - D’après Warren (1030) et Girgis (1071)

Osteoporosis: treatments 28 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) Subtrochanteric fractures and alendronate 20 7 IRR (IC 95) After 6 16 12 8 5 Before 4 3 2 4 1 0 ss 5 ye ar s Before and after periods > 1 - 5 ye ar ar 1 ye < ea rn 1 y < 1 - 5 ye ar s ss ea r ar s 10 y y e 5 - 10 > on at e m Zo le dr nt iu te ro na ro ed is R St fe ne H xi PT al o R e id ro na Ib te an dr on Pa at e m id ro na te Ét on at dr lo C Al en d ro na te 0 è There was an increased risk for subtrochanteric and diaphyseal fractures before starting the treatment against è osteoporosis. This increased risk was especially high in the year preceding start of treatment. With alendronate, such increased risk diminishes progressively with treatment. La Lettre du Rhumatologue ASBMR 2010 - D’après Vestergaard (1072)

Osteoporosis: treatments 29 Incidence of subtrochanteric fractures in the SOF cohort ● 1 396 hip fractures, 45 of which were subtrochanteric fractures Incidence for 10 000 persons-year 150 Femoral → 58, 1/10 000 Intertrochanteric → 49, 1/10 000 Subtrochanteric → 3, 1/10 000 100 50 0 65 -69 70 -74 75 -79 80 -84 85+ Age (years) è Subtrochanteric fractures represent less than 2 % of hip fractures è The incidence of subtrochanteric fractures increases with patient age, with a same pattern as for hip fractures La Lettre du Rhumatologue ASBMR 2010 - D’après Kelly (FR 0355)

Osteoporosis: treatments 30 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) Combined Incidence (%) 3 Controls Diagnostic of breast cancer RR = 0. 74 (0. 66 -0. 84) ; p < 0. 001 Alendronate 2 Death due to breast cancer RR = 0, 52 (0, 40 -0, 68) ; p < 0, 001 1 0 0 2 4 6 8 Years è 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 La Lettre du Rhumatologue ASBMR 2010 - D’après Abrahamsen (SU 0128)

Osteoporosis: treatments 31 Effect of transdermal teriparatide on bone remodeling 200 SC 20 TD 50 TD 80 150 Variations of bone remodeling markers PINP 300 100 50 CTX 300 250 Variations (%) PTH mean value (pg/ml) Comparison of transdermal and subcutaneous pharmacokinetic and pharmacodynamic profiles 250 200 150 * * 100 * * 50 * * *A 0 200 150 100 *B 50 *A 0 * 0 0 1 2 3 4 Hours 5 6 7 8 0 48 72 96 *B 0 Days *A * * *A * 48 72 96 Days *p < 0, 05 versus baseline ; Ap< 0, 05 TD 50 versus TD 80 ; Bp < 0, 01 SC 20 versus TD 80 è Transdermal teriparatide has a pharmacokinetic and a pharmacodynamic profile on the bone remodeling markers comparable to subcutaneous teriparatide 20 g profile. La Lettre du Rhumatologue ASBMR 2010 - D’après Kenan Y et al. , Lod, Israël, abstr. FR 0376, actualisé

Osteoporosis: treatments 32 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 Mapping and significance of cortical thickness modifications (besides the femoral head) Thickness variations (%) 24 months - baseline -2 0, 05 0 2 4 6 8 è 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 La Lettre du Rhumatologue 0, 025 0 p for topographic distribution (a) p = 0, 00000004 (b) p = 0, 00007 (c) p = 0, 00007 ASBMR 2010 - D’après Gee AH et al. , Cambridge, Royaume-Uni, abstr. 1250, actualisé

Osteoporosis: treatments 33 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) Densitometry data characteristics, vitamin. D-calcium contribution Initial caracteristics Type 90 Hz 30 Hz Witnesses Femoral neck 0. 686 (0, 049) 0. 676 (0, 060) 0. 687 (0. 054) Total hip 0. 851 (0, 066) 0. 836 (0, 083) 0. 845 (0. 068) Lumbar spince 0. 904 (0, 090) 0. 890 (0, 069) 0. 902 (0. 080) Trabecular tibial bone 149 (36) 144 (29) 145 (30) Calcium (mg), mean + ET (SD) Total 1 538 (677) 1 399 (656) 1 352 (642) Vitamin D (UI), mean+ ET (SD) Total 866 (582) 778 (583) 808 (584) Metabolic index 352 (224) 337 (237) 383 (227) Mean BMD (g/cm-2), (SD) Mean v. BMD (mg: cm-3), (SD) Phisycal activity (kcal/j), mean (SD) è Beneficial effect in ITT vibrations on BMD has not been demonstrated è Lack of data on muscle evaluation, weight at one year, quality of life, etc. La Lettre du Rhumatologue ASBMR 2010 - D’après Slatkovska (1027)

Osteoporosis: treatments 34 An explosive treatment… nitroglycerin (NTG) ! BMD variations at 24 months 10 NTG ointment 120 21, 3 % (21, 6 à 22, 1) 100 Lumbar spine 8 6 6, 7 % (5, 2 à 8, 2) 4 2 0 0 3 12 Mois -2 50, 8 % (43, 7 à 60, 2) 10 8 6 4 2 0 -2 Urinary NTX 150 100 50 0 Variations (%) Placebo 140 80 Variations (%) PAL osseuses 160 0 3 12 24 Months Variations (%) Markers variations at 12 months 12 24 Months Femoral neck 7, 0 % (5, 5 à 8, 5) 12 24 Months è NTG seems to have beneficial effects on bone remodeling and BMD at 24 months La Lettre du Rhumatologue ASBMR 2010 - D’après Jamal S et al. , Toronto, Canada, abstr. 1252, actualisé