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Chap ter IV.

Chap ter IV. Osteoporosis Treatment. Osteoporosis Treatment 1) Anti-resorptive Agents. 39. Effect of Bazedoxifene on Vertebral Fracture in Postmenopausal Women with Osteoporosis (1). Multicenter, double-blind RCT 7,492 postmenopausal women mean age: 66.4 ± 6.7 yrs

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Chap ter IV.

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  1. Chapter IV. Osteoporosis Treatment

  2. Osteoporosis Treatment 1) Anti-resorptive Agents 39 Effect of Bazedoxifene on Vertebral Fracture in Postmenopausal Women with Osteoporosis (1) • Multicenter, double-blind RCT • 7,492 postmenopausal women • mean age: 66.4 ± 6.7 yrs • osteoporosis (prevalent vertebral fracture [T-score > -4] or T-score < -2.5 in women with no fracture) • randomization into 4 groups • group I : bazedoxifene 20 mg (n = 1,886) • group II : bazedoxifene 40 mg (n = 1,872) • group III : raloxifene 60 mg (n = 1,849) • group IV : placebo (n = 1,835) • duration: 36 months • primary outcome: incidence of new vertebral fracture • secondary outcome: non-vertebral fractures (NVF) + 1,200 mg Ca/d + 400 IU vitamin D La Lettre du Rhumatologue ASBMR 2007 – From Silverman SL et al., Beverly Hills, USA, abstract 1206, updated

  3. Osteoporosis Treatment 1) Anti-resorptive Agents 40 Effect of Bazedoxifene on Vertebral Fracture in Postmenopausal Women with Osteoporosis (2) Incidence of new vertebral fracture (intent-to-treat population 0-36 months) • Results • the reduction in the incidence of new vertebral fractures was (as compared to placebo) • - 42% (RR = 0.58;95% CI [0.38-0.88]) in group I • - 37% (RR = 0.63; 95% CI [0.42-0.96]) in group II • - 42% (RR = 0.58; 95% CI [0.38-0.89]) in group III • there was no treatment effect on NVF • there was no difference between the different groups with regard to adverse effects 4.5 Bazedoxifene 20 mg Bazedoxifene 40 mg 4 Raloxifene 60 mg 3.5 Placebo 3 2.5 * Kaplan-Meier (K-M) fracture rate (%) 2 1.5 1 0.5 0 * p < 0.05 for any active group versus placebo -0.5 0 6 12 18 24 30 36 42 Months • Bazedoxifene significantly reduces the risk of new vertebral fracture in postmenopausal women with osteoporosis La Lettre du Rhumatologue ASBMR 2007 – From Silverman SL et al., Beverly Hills, USA, abstract 1206, updated

  4. Osteoporosis Treatment 1) Anti-resorptive Agents 41 No Impact of Herbal Therapies on Bone Mineral Density in Womenwith Vasomotor Symptoms (1) • Randomized controlled trial comparing 3 herbal therapies and HRT to placebo • 351 peri-/post-menopausal women (with ≥ 2 hot flashes/night sweats/day) • mean age: 52 + 2.5 years • average calcium intake: 727-881 mg/d • 5 treatment groups • Black Cohosh (160 mg/d) • multibotanical (including Black Cohosh 200 mg/d) • multibotanical + soy • CEE + MPA • placebo • Outcome measures: lumbar spine and hip BMD at 6 and 12 months • 93% of included women completed the 1-year study La Lettre du Rhumatologue ASBMR 2007 - From Newton KM et al., Seattle, USA, abstract S339, updated

  5. Osteoporosis Treatment 1) Anti-resorptive Agents 3 3 Multi + Soy Black Cohosh 2 2 Placebo Multi HT 1 1 0 0 -1 -1 -2 -2 6 Months 12 Months 6 Months 12 Months -3 -3 42 No Impact of Herbal Therapies on Bone Mineral Density in Womenwith Vasomotor Symptoms (2) Spine - Percent change from baseline Hip - Percent change from baseline p = 0.0001 p = 0.002 p = 0.04 • Black Cohosh alone or as part of a multibotanical preparation has no impact on BMD of the total hip or lumbar spine La Lettre du Rhumatologue ASBMR 2007 - From Newton KM et al., Seattle, USA, abstract S339, updated

  6. Osteoporosis Treatment 1) Anti-resorptive Agents FN T-score > -2 1.41 -2.5 < T-score < -2 0.79 FN T < -2.5 0.50 No BL vert fx 0.86 (0.59-1.3) All women 1.00 (0.75-1.3) 1.0 10.0 0.1 No. fx = 109 RR (95% CI) 43 Efficacy of Continued Alendronate for Fractures in Women without Prevalent Vertebral Fracture: the FLEX Trial Non-spine Fractures p for interaction = 0.019 La Lettre du Rhumatologue ASBMR 2007 – From Schwartz AV et al., San Francisco, USA, abstract 1057, updated

  7. Once weekly oral RIS improves BMD and prevents excess bone resorption in breast cancer survivors, even in women treated by an aromatase inhibitor (AI) Osteoporosis Treatment 1) Anti-resorptive Agents 44 Risedronate Prevents Bone Loss in Breast Cancer Survivors:a Two-Year, Randomized, Double-Blind, Placebo-Controlled Clinical Trial Mean percent change ± standard error in BMD at 24 months Placebo + AI(n = 18) Risedronate + AI(n = 20) Placebo + No AI(n = 26) Risedronate + No AI(n = 23) 6 * p < 0.05 ** p < 0.01 from baseline † p < 0.05 between groups * 4 * † † † 2 Change in mineral density (%) 0 -2 * -4 ** † † * * ** -6 ** ** PA Spine Lateral Spine Total Hip Trochanter ASBMR 2007 - From Greenspan SL et al., Pittsburgh, USA, abstract 1017 updated La Lettre du Rhumatologue

  8. In this study, for patients already at risk, risedronate was sufficient to prevent a decrease in BMD and an increase in bone turnover Osteoporosis Treatment 1) Anti-resorptive Agents 45 SABRE (Study of Anastrozole with the Bisphosphonate Risedronate)12-Month Analysis Percentage change in BMD p = 0.0001* 5 Lumbar spine 4 Total hip p < 0.0001* p = 0.0112* 3 Estimated % change in BMD from baseline to 12 months 2 p = 0.4918* 1 p = 0.3511* 0 -1 p < 0.0020* -2 Treatment: Anastrozolealone Anastrozole+ placebo Anastrozole+ risedronate Anastrozole+ risedronate Stratum: Lower risk Moderate risk Higher risk ASBMR 2007 - From Eastell R et al., Sheffield, United Kingdom, abstract S300, updated La Lettre du Rhumatologue

  9. Osteoporosis Treatment 1) Anti-resorptive Agents 46 Efficacy and Safety of Zoledronic Acid 5 mg in Preventing Fractures in Men and Women with Prevalent Hip Fracture: the HORIZON-Recurrent Fracture Trial (1) Zoledronic Acid 5 mg reduced cumulative 3-year risk of clinical fracture by 35% over time 20 Hazard Ratio: 0.65 (95% CI: 0.50-0.84)p = 0.0012Absolute risk reduction: 5.3% 16 35% 12 Cumulative incidence (%) 8 Zoledronic, 5 mg (n = 1,065)Placebo (n = 1,062) 4 0 0 4 8 12 16 20 24 28 32 36 Months No. at Risk Zoledronic 5 mg :Placebo : La Lettre du Rhumatologue ASBMR 2007 – From Lyles K et al., Durham, USA, abstract 1055, updated

  10. Osteoporosis Treatment 1) Anti-resorptive Agents 47 Efficacy and Safety of Zoledronic Acid 5 mg in Preventing Fractures in Men and Women with Prevalent Hip Fracture: the HORIZON-Recurrent Fracture Trial (2) Zoledronic Acid 5 mg reduced risk of all cause mortality by 25% over time Zoledronic, 5 mg (n = 1,065)Placebo (n = 1,062) 16 28% 12 Cumulative incidence (%) 8 4 Hazard Ratio: 0.72 (95% CI: 0.56-0.93)p = 0.0117Absolute risk reduction: 3.7% 0 0 4 8 12 16 20 24 28 32 36 Months La Lettre du Rhumatologue ASBMR 2007 – From Lyles K et al., Durham, USA, abstract 1055, updated

  11. Osteoporosis Treatment 1) Anti-resorptive Agents 48 Risk Factors for Serious Adverse Events (SAEs) of Atrial Fibrillation in the HORIZON-PFT Trial of Zoledronic Acid CHF: congestive heart failure La Lettre du Rhumatologue ASBMR 2007 – From Cummings SR et al., San Francisco, USA, abstract 1056, updated

  12. Osteoporosis Treatment 1) Anti-resorptive Agents 49 Osteonecrosis of the Jaw Under Bisphosphonate (BP) Therapy:Patient Profile and Risk AssessmentLarge Systematic Review in Germany (1) • Ongoing German Register for Osteonecrosis of the Jaw (ONJ) • Standardized questionnaire • Results on 614 registred cases • Indications for BP treatment : – 76.8%: cancer – 5%: osteoporosis – 18.2%: osteoporosis + cancer • Type of malignancy : – breast: 44% – kidney: 4% – multiple myeloma: 33% – lymphoma: 2% – prostate: 15% – others: 3% La Lettre du Rhumatologue ASBMR 2007 – From Jung TI et al., Berlin, Germany, abstract S298, updated

  13. Osteoporosis Treatment 1) Anti-resorptive Agents 50 Osteonecrosis of the Jaw Under Bisphosphonate (BP) Therapy:Patient Profile and Risk AssessmentLarge Systematic Review in Germany (2) Time of BP intake until diagnosis of ONJ in patients taking a single type of BP Success Rate of Different Treatment Regimens Against ONJ % 100 Success Partial Success No Success BP Mean time Cases (months) (n) Alendronate 36  26 4 Ibandronate 29  22 5 Pamidronate 51  35 19 Zoledronate 23  12 147 80 59 60 52 Number of patients treated in percent 38 34 40 28 28 24 20 17 20 0 Conservative (N = 29) Surgical (N = 25) Combined (N = 71) La Lettre du Rhumatologue ASBMR 2007 – From Jung TI et al., Berlin, Germany, abstract S298, updated

  14. Osteoporosis Treatment 1) Anti-resorptive Agents 51 ASBMR Task Force on Bisphosphonate-Associated Osteonecrosis of the Jaw (ONJ) [1] • Definition • confirmed case: area of exposed bone in maxillofacial region that did not heal within 8 weeks after identification by health care provider + use of bisphosphonate + no radiation therapy in craniofacial region • suspected case: < 8 weeks • Additional signs: pain, swelling, paresthesia, suppuration, soft tissue ulceration, intra- or extra-oral tracks, loosening of teeth, radiographic variability • Risk factors: IV bisphosphonates (BP), cancer and anti-cancer therapy, dental extraction, oral bone manipulating surgery, poor fitting dental appliance, intra oral trauma, duration of exposure to BP, glucocorticoids, alcohol, tobacco, pre-existing dental or periodontal disease • Unknown incidence of ONJ in the general population non exposed to BP BP for osteoporosis: 57 cases of ONJ reported; Paget’s disease: 7 cases reported Estimated incidence with oral BP: 1 to 10/100,000/yr La Lettre du Rhumatologue ASBMR 2007 – From Khosla S, Rochester, USA, Joint ECTS/ASBMR Session on ONJ, updated

  15. Osteoporosis Treatment 1) Anti-resorptive Agents 52 ASBMR Task Force on Bisphosphonate-Associated Osteonecrosis of the Jaw (ONJ) [2] Recommendations for patients with osteoporosis initiating or alreadyreceiving bisphosphonates therapy • Advise patients that the risk of bisphosphonate-associated ONJ with routine oral therapy for osteoporosis is low • Encourage to maintain good oral hygiene, regular dental visits and urge to report any oral problem • Not necessary to recommend dental examination before starting oral bisphosphonate La Lettre du Rhumatologue ASBMR 2007 – From Khosla S, Rochester, USA, Joint ECTS/ASBMR Session on ONJ, updated

  16. Osteoporosis Treatment 1) Anti-resorptive Agents 53 ASBMR Task Force on Bisphosphonate-Associated Osteonecrosis of the Jaw (ONJ) [3] Recommendations for patients with osteoporosis already receiving bisphosphonates therapy (> 3 yrs) • Patients with periodontal disease should receive appropriate non-surgical therapy • Oral bisphosphonates are not a contra-indication for dental implant placement • Endodontic treatment is preferable to extraction or periapical surgery • If an invasive dental procedure is anticipated, some experts suggest stopping bisphosphonates for a period before and after the procedure La Lettre du Rhumatologue ASBMR 2007 – From Khosla S, Rochester, USA, Joint ECTS/ASBMR Session on ONJ, updated

  17. Osteoporosis Treatment 1) Anti-resorptive Agents 54 Giant Osteoclast Formation after Long-Term Oral Aminobisphosphonate Therapy for Postmenopausal Osteoporosis Giant hypernucleated osteoclast after long-term alendronate 400x 630x 400x Nuclear profile 0.16 less than 8 8 to 12 0.12 13 to 20 Osteoclasts/mm² more than 20 0.08 0.04 Placebo 1 mg 5 mg 10 mg 20/0 mg La Lettre du Rhumatologue ASBMR 2007 – From Weinstein RS et al., Little Rock, USA, abstract 1058, updated

  18. Osteoporosis Treatment 1) Anti-resorptive Agents 55 Effect of Denosumab on Bone Mineral Density and Bone Turnover Markers: 48-Month Results (1) Effect of 4 years of denosumab treatment on lumbar spine BMD Effect of 4 years of denosumab treatment on serum CTX level Serum CTx 14 Placebo 60 12 Denosumab 60 mg 40 10 20 p < 0.001 10.3 8 9.0 0 6 7.2 Percent change (LS Mean + SE) Percent change (serum CTx mean ± SE) -20 4 -40 2 -60 0 -80 -2 -1.3 -1.8 -2.4 -4 -100 0 3 6 12 18 24 36 48 0 12 24 36 48 Months Months La Lettre du Rhumatologue ASBMR 2007 – From Miller P et al., Lakewood, USA, abstract 1205, updated

  19. Osteoporosis Treatment 1) Anti-resorptive Agents * * * * 0 3 6 12 18 24 36 48 56 Effect of Denosumab on Bone Mineral Density and Bone Turnover Markers: 48-Month Results (2) Lumbar spine BMD Serum CTx 14 100 Discontinuedtreatment Retreatment60 mg QSM Discontinuedtreatment Retreatment60 mg QSM 12 80 * 8.8 10 60 9 8 40 6 20 Percent change (LS Mean + SE) 4 0 Percent change (serum CTx median + SE) 2 -20 1 -40 0 * -60 -2 -1.3 -1.8 -2.4 -80 -4 -100 -6 0 12 24 36 48 Months Months *p<0.05 Placebo Denosumab 30 mg La Lettre du Rhumatologue ASBMR 2007 – From Miller P et al., Lakewood, USA, abstract 1205, updated

  20. Osteoporosis Treatment 1) Anti-resorptive Agents 57 Denosumab Increases Bone Mineral Density in Patients with Rheumatoid Arthritis: 12-month Results Denosumab increased femoral neck BMD over 12 months PlaceboDenosumab 60 mg (n = 70)Denosumab 180 mg (n = 71) 5 * p < 0.01 versus placebo 4 3 2 Percent change from baseline (mean 95% CI) * 1 * 0 -1 -2 Baseline 1 month 6 months 12 months • Denosumab administered subcutaneously every 6 months significantly increased BMD in patients with rheumatoid arthritis compared with placebo La Lettre du Rhumatologue ASBMR 2007 – From Dore RK et al., Anaheim, USA, abstract 1208, updated

  21. Osteoporosis Treatment 1) Anti-resorptive Agents 58 A Randomized, Double-Blind, Placebo-Controlled Study of a Cathepsin K Inhibitor (odanacatib) in the Treatment of Postmenopausal Osteoporosis (1) s-CTx Urine Deoxypyridinoline/Creatinine 40 40 30 20 20 0 10 -20 0 % change from baseline % change from baseline -40 -10 -20 -60 -30 -80 -40 -100 -50 0 1 3 6 12 0 1 3 6 12 w1 Months Months w1 Placebo MK-0822 25 mg MK-0822 3 mg MK-0822 50 mg MK-0822 10 mg La Lettre du Rhumatologue ASBMR 2007 – From Bone HG et al., Detroit, USA, abstract 1128, updated

  22. Osteoporosis Treatment 1) Anti-resorptive Agents 59 A Randomized, Double-Blind, Placebo-Controlled Study of a Cathepsin K Inhibitor (odanacatib) in the Treatment of Postmenopausal Osteoporosis (2) s-BSAP s-P1NP 50 60 40 40 30 20 20 % change from baseline % change from baseline 10 0 0 -10 -20 -20 -40 - 30 0 1 3 6 12 0 1 3 6 12 Months w1 Months w1 Placebo MK-0822 25 mg MK-0822 3 mg MK-0822 50 mg MK-0822 10 mg La Lettre du Rhumatologue ASBMR 2007 – From Bone HG et al., Detroit, USA, abstract 1128, updated

  23. Osteoporosis Treatment 1) Anti-resorptive Agents 4.0 3.0 2.0 1.0 0 -1.0 60 A Randomized, Double-Blind, Placebo-Controlled Study of a Cathepsin K Inhibitor (odanacatib) in the Treatment of Postmenopausal Osteoporosis (3) Percent change from baseline (mean ± SE) - Last observation carried forward Placebo MK-0822 3 mg MK-0822 10 mg MK-0822 25 mg MK-0822 50 mg Weighted lumbar spine mean percent changefrom baseline 0 1 3 6 12 Months La Lettre du Rhumatologue ASBMR 2007 – From Bone HG et al., Detroit, USA, abstract 1128, updated

  24. Osteoporosis Treatment 2) Anabolics Agents 12.3% (p < 0.001) 25 25 20.1 20 20 Mean % change in spine BMD 15 15 12.4 Number with BMD > 20% 7.8 7.6 10 10 7 2 5 5 0 0 0 0 1 2 3 4 1 2 3 4 Quartile of 1 month P1NP Quartile of 1 month P1NP 61 Prediction of 24 Month Change in BMD on PTH Followed by Alendronate: The PaTH Study 2 year BMD change by quartile of 1 month P1NP (n = 53) Number with spine BMD increase > 20 % by quartile of 1 month P1NP Mean BMD increase by quartile of 1 month P1NP • A single measurement of P1NP as early as 1 month after initiation of PTH therapy strongly predicts 2 year spine BMD response to 1 year of PTH followed by 1 year of ALN La Lettre du Rhumatologue ASBMR 2007 – From Black DM et al., San Francisco, USA, abstract 1090, updated

  25. Osteoporosis Treatment 2) Anabolics Agents 160 0.7 Switch Switch Switch 140 0.6 120 0.5 100 Median serum PINP (ng/ml) 0.4 Median serum CTx (ng/ml) 80 Add Add 0.3 60 0.2 40 0.1 20 0 0 0 1 3 6 0 1 3 6 Months Months 62 Efficacy of Adding Teriparatide versus Switching to Teriparatide in Postmenopausal Osteoporotic Women Previously treated with Raloxifene or Alendronate PINP CTx Teriparatide after Alendronate (n = 50) Teriparatide after Raloxifene (n = 49) Teriparatide + Alendronate (n = 52) Teriparatide + Raloxifene (n = 47) La Lettre du Rhumatologue ASBMR 2007 – From Cosman F et al., West Haverstraw ,USA, abstract 0423, updated

  26. Osteoporosis Treatment 2) Anabolics Agents 63 BMD and Bone Markers Changes after Teriparatide Treatment: Differences According to Previous Treatment with Alendronate or Risedronate The OPTAMISE Study (1) • Multinational, open-label, parallel group study, in postmenopausal women who have taken risedronate (RIS) [n = 146] or alendronate (ALN) [n = 146] for ≥ 2 years • Women selection • lumbar spine or total hip T-score • US and Australia: ≤ -2.5 or ≤ -2 and ≥ 1 prevalent osteoporotic fracture* • Europe and Canada: < -2.5 and 1 prevalent osteoporotic fracture* • no other treatment for osteoporosis within 36 months before study entry • no systematic glucocorticoids or anabolic steroids within 3 months Screening Subgroup StratificationBisphosphonatediscontinued duringscreening period Prior bisphosphonateTherapy > 2 years Daily TPTD for 12 months Prior Risedronate5 mg/d or 30-35 mg/wk Teriparatide only20 mcg/d Prior Alendronate10 mg/d or 70 mg/wk * according to teriparatide label in different countries ASBMR 2007 – From Miller P et al., Lakewood, USA, abstract 1091, updated Delmas P et al., Lyon, France, abstract 1092, updated La Lettre du Rhumatologue

  27. Osteoporosis Treatment 2) Anabolics Agents 64 BMD and Bone Markers Changes after Teriparatide Treatment: Differences According to Previous Treatment with Alendronate or Risedronate The OPTAMISE Study (2) Lumber Spine DXA QCT 12-Month change from baseline 30 6 Prior RIS (n = 112) Prior ALN (n = 119) 5.1%* Prior ALN6 mo (n = 143)12 mo (n = 137) Prior RIS6 mo (n = 138)12 mo (n = 129) 25 5 * p = 0.0123 p = 0.019 3% 20 4 p = 0.013 24.1% 15 3 BMD percent change from baseline Percent change from baseline 3.6% 10 2 13.7% 2% 5 1 6.1% 3.5% 0 0 Integral Spine Trabecular Spine BL 12 Months 6 Total Hip DXA QCT 12-Month change from baseline 1 Prior ALN6 mo (n = 142)12 mo (n = 136) Prior RIS6 mo (n = 136)12 mo (n = 128) p = 0.0586 -0.3%* 12 Prior RIS (n = 100) 13.2% Prior ALN (n = 118) 0 8 -1.2% 5.1% -1 6 BMD percent change from baseline * p = 0.0059 p = 0.0672 Percent change from baseline 4 -2 0.6% -0.5% -1.7% 0 -1.9% -3 Integral TotalHip TrabecularTotal Hip BL 6 12 Months ASBMR 2007 – From Miller P et al., Lakewood, USA, abstract 1091, updated Delmas P et al., Lyon, France, abstract 1092, updated La Lettre du Rhumatologue

  28. Osteoporosis Treatment 2) Anabolics Agents 65 BMD and Bone Markers Changes after Teriparatide Treatment: Differences According to Previous Treatment with Alendronate or Risedronate The OPTAMISE Study (3) Bone Turnover Markers after 3 months Prior RIS (n = 146) Prior ALN (n = 146) Prior RIS (n = 146) Prior ALN (n = 146)1 *p < 0.01**p < 0.001 100 p < 0.001 5 ** ** 80 41%difference 4 * 60 Mean change from baseline(ng/ml) Ratio to baseline 3 40 ** 2 ** 20 0 1 Month 3 P1NP P1NP BAP OC CTX NTX 1BAP (n = 145) Bone Turnover Marker • In response to teriparatide, subjects previously treated with risedronate showed greater increase in bone turnover markers • However, no data on fracture are available ASBMR 2007 – From Miller P et al., Lakewood, USA, abstract 1091, updated Delmas P et al., Lyon, France, abstract 1092, updated La Lettre du Rhumatologue

  29. Osteoporosis Treatment 2) Anabolics Agents 66 Bone Apposition in Patients on Teriparatide Treatment is Preferably Directed to Skeletal Regions of Local Structural Weakness: Assessment by High Resolution CT-Based Finite Element Analysis in Vivo (1) High Resolution CT Helical CT of T12, ~89 slices 3-D structuralanalysis densitometry 3-D active shapesegmentation Calibration to mineral scale La Lettre du Rhumatologue ASBMR 2007 – From Graeff C et al., Kiel, Germany, abstract 1267, updated

  30. Osteoporosis Treatment 2) Anabolics Agents 67 Bone Apposition in Patients on Teriparatide Treatment is Preferably Directed to Skeletal Regions of Local Structural Weakness: Assessment by High Resolution CT-Based Finite Element Analysis in Vivo (2) FE analysis: Mechanical Behavior • FE: Simulated mechanical loadingallows assessment of local strain • Uni-axial compression test La Lettre du Rhumatologue ASBMR 2007 – From Graeff C et al., Kiel, Germany, abstract 1267, updated

  31. Osteoporosis Treatment 2) Anabolics Agents 68 Bone Apposition in Patients on Teriparatide Treatment is Preferably Directed to Skeletal Regions of Local Structural Weakness: Assessment by High Resolution CT-Based Finite Element Analysis in Vivo (3) • Bone apposition under TPTD treatment is not uniform but directed to skeletal regions of local structure weakness • Bone apposition under treatment is following biomechanical principles A. Bone apposition versus baseline strain B. Bone apposition versus baseline BV/TV 25 25 all: p < 0.0001 20 20 R² = 0.90 15 15 R² = 0.97 Local BMD change (mg/cc) at follow-up Local BMD change (mg/cc) at follow-up 10 10 6 months 5 5 R² = 0.95 12 months 24 months 0 0 0.0 0.2 0.4 0.6 0.0 0.2 0.4 0.6 Local relative strain (baseline) Local bone volume fraction (baseline) Uniform local bone apposition independent of baseline BV/TV Strong logarithmic correlation with local strain La Lettre du Rhumatologue ASBMR 2007 – From Graeff C et al., Kiel, Germany, abstract 1267, updated

  32. Osteoporosis Treatment 2) Anabolics Agents Buckling Ratio Section Modulus Max. ns ns * ns ns ns ns Strength increases in second year of therapy Strength increases in second year of therapy ** 69 Effects of 2 year Teriparatide Treatment on 3-D Femoral Neck Bone Distribution, Geometry and Bone Strength: Results from the Eurofors Study • 2 year treatment with TPTD results in significant improvement in bending strength and buckling strength • Increases in bending and buckling strength are caused by endosteal apposition Bending strength under TPTD treatment Buckling risk under TPTD treatment Section Modulus Min. * 4% 4% 2% 2% 0% 0% Change (mean + SEM) Change (mean + SEM) -2% -2% -4% -4% -6% -6% Baseline 6 months 12 months 24 months Baseline 6 months 12 months 24 months * p < 0.05 ** p < 0.001 La Lettre du Rhumatologue ASBMR 2007 – From Borggrefe J et al., Kiel, Germany, abstract 1269, updated

  33. Osteoporosis Treatment 2) Anabolics Agents 70 Comparison of the Effects of Teriparatide and Alendronate on Parameters of Total Hip Strength as Assessed by Finite Element Analysis: Results from the Forteo and Alendronate Comparison Trial FE-predicted total hip strength, total hip average density and the ratio of strength/density 12 * 10 ALN TPTD * 8 6 4 % change from baseline(with interquartile range) 2 0 -2 * p < 0.05 -4 -6 Total HipStrength Total HipAverage density 6 Mo Strength/Density Total HipStrength Total HipAverage density 18 Mo Strength/Density • Total hip strength at 18 months significantly increased in the TPTD group and did not significantly change in the ALN group. This significant biomechanical effect for TPTD was associated with a significant decrease in cortical density and a somewhat larger increase in trabecular density La Lettre du Rhumatologue ASBMR 2007 – From Keaveny TM et al., Berkeley, USA, abstract 1089, updated

  34. Osteoporosis Treatment 2) Anabolics Agents 71 Effects of One Year Treatment with PTH (1-34) on Bone Microstructure at the Ultradistal Radius • These data (pilot study) represent the first assessment of trabecular microstructure at the wrist following PTH therapy • The beneficial effects of PTH (1-34) at the ultradistal (UD) radius seem to result from an increase in thickness of pre-existing trabeculae with only a minor increase in trabecular number • PTH (1-34) treatment does not seem to affect cortical bone at the UD radius High resolution 3D-pQCT results (n = 8) 12 ** 10 ** * p < 0.05** p < 0.01*** p = 0.07 versus bsl 8 * 6 % change from bsl 4 *** 2 0 -2 -4 Tb.vBMD Cort.vBMD TotalvBMD BMD Tb. Th Tb. N Cort. Th La Lettre du Rhumatologue ASBMR 2007 – From Kirmani S et al., Rochester, USA, abstract 1085, updated

  35. Osteoporosis Treatment 2) Anabolics Agents Placebo 30 µg 7.5 µg 45 µg 15 µg 72 Ostabolin-CTM Increases Lumbar Spine and Hip BMD after 1 Year of Therapy: Results of a Phase II Clinical Trial Early onset of bone formation:% change from baseline in serum P1NP levels Delayed stimulation of bone resorption:% change from baseline in serum CTx levels * p < 0.05, ** p < 0.001 * p < 0.05, ** p < 0.001 140 250 120 ** 200 ** 100 ** ** ** 80 * 150 ** ** ** * ** 60 ** * 100 ** Mean % change (+ SEM) 40 20 * 50 0 0 -20 -50 -40 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Months Months La Lettre du Rhumatologue ASBMR 2007 – From Hodsman A et al., London, Canada, abstract 1130, updated

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