CHAPTER II Osteoporosis: treatments
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 : " long term " group " 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 BL Treatment duration (years) Lumbar BMDTotal hip BMD BMD variation (%, CI 95 ) DenosumabPlacebo * * * * * * * * * * * * *p < 0,002 versus placebo and baseline values ,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 D’après Papapoulos (1025) 20 Osteoporosis: treatments
La Lettre du Rhumatologue ASBMR 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 (%) ml/mn (n = 73) ml/mn (n = 2 817) ml/mn (n = 4 069) > 90 ml/mn (n = 842) Lumbar 5.0 ( ) 8.9 ( ) 9.0 ( ) 8.1 ( ) Femoral neck 5.9 ( ) 5.1 ( ) 5.2 ( ) 5.6 ( ) Total hip 5.9 ( ) 6.4 ( ) 6.4 ( ) 5.8 ( ) N All patients ml/mn ml/mn ml/mn > 90 ml/mn 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
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, ,5 -1,5 0,5 2,5 2 1,5 1 Z6 Z3P3 Ans Evolution (%) 1 % p < 0,001 Femoral neck BMD 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 D’après Black (1070) 22 Osteoporosis: treatments
La Lettre du Rhumatologue ASBMR 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 Zoledronic acid Placebo p = p < n = 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 % %< Clinical vertebral fractures 1456 % 0.12 (NS) 6466 %< Nonvertebr al fractures 9324 % 0.16 (NS) %< Cumulated events (%) RR : 0.68p = 0.04 Follow-up duration: 3 years RR : 0.66p < Osteoporosis: treatments Cumulated events (%) Months
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 Bisphosphonate generics : a rapid disintegration ASBMR D’après Olszynski (FR0390) 24 Osteoporosis: treatments
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
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 Incidence Incidence (%) Women Men Women Men Subtrochanteric fracturesHip fractures ASBMR D’après Wang (1029) 26 Osteoporosis: treatments
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 ( ), 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 ( ), p < 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 Atypical Typical 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 D’après Warren (1030) et Girgis (1071) 27 Osteoporosis: treatments Are patients who received long acting bisphosphonates at risk for atypical fractures ?
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 = ) was matched, after adjustment for age and sex, with 3 controls (n = ) 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 IRR (IC 95 ) > 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 D’après Vestergaard (1072) 28 Osteoporosis: treatments
La Lettre du Rhumatologue ASBMR D’après Kelly (FR0355) Incidence of subtrochanteric fractures in the SOF cohort ● 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/ Intertrochanteric → 49,1/ Subtrochanteric → 3,1/ Age (years) Incidence for persons-year 29 Osteoporosis: treatments
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 – users –4 centrals matched for to age and sex (n = ) 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 Combined Incidence (%) Years Controls Alendronate Diagnostic of breast cancer RR = 0.74 ( ) ; p < Death due to breast cancer RR = 0,52 (0,40-0,68) ; p < 0,001 ASBMR D’après Abrahamsen (SU0128) 30 Osteoporosis: treatments
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 D’après Kenan Y et al., Lod, Israël, abstr. FR0376, actualisé SC20 TD50 TD 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
La Lettre du Rhumatologue ASBMR 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 (%) ,050,025 0 p for topographic distribution (a) p = 0, (b) p = 0,00007 (c) p = 0, Osteoporosis: treatments
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 D’après Slatkovska (1027) 33 Osteoporosis: treatments
La Lettre du Rhumatologue ASBMR 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) !