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New drugs for osteoporosis therapy: a review of the clinical trials phase 2 and 3

New drugs for osteoporosis therapy: a review of the clinical trials phase 2 and 3 to identify if a study meets the specified criteria. For the articles unavailable in full length the corresponding authors were contacted. All collected articles were included into further analysis. Selection of studies Only articles that published the results of the CTP 2 and CTP3 were included in the review process. Studies comparing an intervention to placebo or to another intervention were eligible for inclusion. The studies were selected if they met the endpoints, measurement of bone mineral density (BMD) and/or bone turnover markers (BTM). The articles which did not measure BMD and/or percentage change of BMD compared to baseline values as an endpoint were excluded. Also, studies that examined drug efficacy in patients with secondary osteoporosis (breast, ovarian or prostate cancer) were excluded. There were no limits regarding the patient's gender, duration or type of the study, and pharmacological classification of drug for osteoporosis treatment. Types of outcome measures Studies that reported values of BMD and BTM were considered for this review. Studies that measured BMD by Dual-energy x-ray absorptiometry (DXA) on the total hip (TH), femoral neck (FN), lumbar spine (region L1-L4) (L), and forearm (distal radius) and presented BMD change in g/cm2 or as a percentage change (a difference between the values of BMD at the end of the study versus baseline value) were included. Bone turnover is associated with the low BMD and high fracture risk (5). BMD changes in a short-term period can be well predicted by changes of biochemical markers (17). Changes in bone metabolism can be faster assessed by measuring of BTM than BMD. Therefore, early assessment of efficacy of osteoporosis therapy should be followed by the values of BTM (18). Two groups of well-known BTM are used: bone formation and bone resorption markers. Frequently used biochemical bone formation markers are specific for collagen formation (osteocalcin (OC), bone-specific alkaline phosphatise (BSAP) and amino-terminal propeptide of type 1 collagen (PI NP)). Mostly used resorption markers are deoxypyrolidinoline, amino- and carboxy­terminal cross-linked telopeptides of type 1 collagen (NTX, CTX) (19). BTM can be measured in serum (BSAP, OC, CTX, PINP) or urine (NTX, Urinary deoxypyridinoline (DPD)) according to the reference methods. Efficacy evaluation Efficacy of medicines for osteoporosis treatment was examined as the percentage change of BMD or/and change in BTM (decrease during the therapy with antiresorptive agents or increase during the therapy with anabolic agents). The fracture risk, if reported, was also examined in all selected articles. Figure 1. Article selection In the analyzed articles, all five drugs increased L BMD in the range from 2.1% (risedronate 100 mg per os, once monthly during 6 months) (22) to 11.3% (TPTD 20 g daily subcutaneous injection during 6 months) (Table 1) (20, 22, 23). Two studies demonstrated that after one-year treatment with denosumab (60mg subcutaneous (sc) injection every 6 months) the increase of BMD was the highest in L spine in comparison with other skeletal sites (21, 24). One-year treatment study conducted by Kendler et al. showed that the improvement of BMD after denosumab treatment was significantly higher (3%, p <0.05) at the L site, as well as at the TH site (1,9%, p<0.001) in comparison to alentronate (70 mg once weekly) (24). Miller et al. showed a constant increase of the L BMD with the same doses of denosumab therapy during the two-year extension study (BMD T-score - 2,14 in the beginning and -1,55 in the end of the study, without specified level of significance) (21). All three articles that described TPTD efficacy showed significant increase only for L spine (20, 23, 25). As TPTD is a peptide hormone, it cannot be given orally and currently can only be administered as a daily sc injection. A new transdermal administration of TPTD made its application more convenient. Increase of TH BMD was significant (p<0.05) after 6-month administration of 40 g daily TPTD transdermal-patch (1.33% change) in comparison to placebo-patch (-0.63% change), and 20 g daily TPTD sc injection (0.09% change). Other daily TPTD transdermal-patch doses (20 g and 30 g), did not show significant improvement of BMD at TH region, unlike L region where all examined TPTD transdermal-patch doses showed significant improvement (~3% for dose of 20 g; ~3.5% for dose of 30 g; ~5% for RESULTS After the initial search of the PubMed and Scopus databases, 57 articles were identified. Forty-two articles were excluded by the title after abstract review or because they did not meet the required criteria. Nine articles were not available in full text format, however, four of them were obtained from the corresponding authors. The final review included 10 articles (Figure 1). In selected articles, all studies recruited postmenopausal women for the analysis except one (20). Half of the articles published the results of multicenter international clinical trials. Measurement of BMD on L spine was performed in all the studies, and in some of them BMD was additionally measured on the forearm (F), proximal femur (PF), TH and/or trochanter (Trc). In all the studies, patients were taking additional supplements of calcium and/or vitamin D. Selected articles examined efficacy of five different drugs: denosumab, TPTD, arzoxifene, risedronate and bazedoxifene (Table 1). Value of BMD at the end of the study versus baseline value is a useful indicator of medication efficacy, but only one article presented both values. All other studies showed their results as BMD percentage change without specifying what was the BMD value at the end of the study (21). Studies' aims, main results, baseline BMD and percentage of its change at the end of the study were presented in Table 1. dose of 40 g, p<0.001) in comparison to baseline values and placebo (25). Another study showed better results of daily sc. injection form of TPTD in TH region. Increase of BMD at the TH (2.66%, p<0.001) was statistically significant after first 12 months of therapy in comparison to baseline. Follow-up therapy (from 12 to 24 months), showed continuous but not statistically significant increase of TH BMD (20). New monthly oral therapeutic regiment of risedronate was also examined as a more convenient way of application. Doses of 100, 150 or 200mg once a month showed efficacy similar to standard 5 mg daily dose after a 6-month therapy. Percentage changes of L BMD was not significantly different between applications of risedronate daily regimen (~3%) and monthly regimens: ~2% (100 mg monthly); ~3% (150 mg monthly); ~3,4% (200 mg monthly) (22). Investigation of new therapeutic regimen of risedonate therapy of 75 mg at two consecutive days a month showed similar efficacy (L BMD+3,4%) to standard daily dose (L BMD+3,6%) after one year of application (26). Arzoxifene (20 mg/daily, per os, during two years of application) showed a significant increase of BMD at the level of p<0.001 at the L and TH region (2.92%, 2.19%, p<0.001) compared with placebo (27). Bazedoxifene (20 mg/daily and 40 mg/daily, per os, during 3 years of application) showed a similar efficacy as raloxifene 60mg compared with placebo (percentage change in L spine was 2.21%, 2.38%, 2.96, p <0.001 respectively; percentage change in TH was 0.27 %, 0.50%, 0.90, p<0.001, respectively) (27, 28). From 10 selected articles only one reported data about fracture risk. Silverman et al. have reported that bazedoxifene (20mg, 40mg daily) and raloxifene significantly reduced the risk of new vertebral fractures after 36 months of therapy compared to placebo (42%, 37%, 42%, respectively) (28). DISCUSSION This review presented efficacy of osteoporosis drugs that are currently in clinical trials phase 2 and 3. Beside efficacy of new drugs, some of the studies tested new dosing regimens, or new ways of application of existing drugs. All the reviewed studies showed that the examined drugs increased more BMD in L spine region than in the hip region. Denosumab has high specificity and affinity for RANKL (6, 11, 29), and pharmacokinetic properties that allow its application once per every six months (11). This dosing regimen enables better adherence. Denosumab therapy (60 mg sc every 6 months) showed a modest efficacy. After six years of therapy with denosumab, the improvement in BMD was about 3% in L spine and 1% in TH region (21). In the study conducted by McClung et al. denosumab applied in different therapeutic regimens (6, 14 or 30 mg sc every three months or 14, 60, 100, or 210 mg sc every six months) after 12 months of therapy showed a similar efficacy (L spine: 3.0-6.7%, TH: 1.9-3.6%) (30). The study conducted by Kendler et al. showed that after switching therapy from alendronate (70 mg weekly, per os) to denosumab (60 mg/6 months, sc), increase of BMD in L and TH was significantly (p<0.0001) higher during the 12-month therapy (BMD % change in L spine: 1.85%, 3.03%, respectively; and TH region: 1.05%, 1.90%, respectively). After switching, the adherence was better with 60mg/6 months denosumab therapy. The interesting fact was that BTM at the end of the study reached almost the baseline value in subjects continuing on alendronate but not in the denosumab group (24). Study conducted by Miller et al. examined effects of denosumab discontinuation after a two-year treatment (210 mg/6months, sc). Discontinuation period lasted one year. At the end of that period BMD decreased by 6.6% at the L spine and 5.3% at the TH. After discontinuation period, retreatment was continued with denosumab sc 60 mg/6 months dose for a period of one year. At the end of retreatment period, BMD was increased by 9% in L spine and 3.9% in the total hip compared to the baseline values (31). TPTD daily sc application, showed the best efficacy in BMD improvement in all measured skeletal regions (LS, TH and FN) in comparison to all examined drugs in this review (20, 25). Study conducted by Miyauchi et al. demonstrated that treatment with TPTD 20 g/day sc. inj constantly improved BMD during the two-year study period compared to baseline values (20). TPTD daily sc application was uncomfortable, thus a new formulation of TPTD as transdermal patches was developed. The best results were achieved with 40 g TPTD patch at the L spine (improvement about 5%) (25). Review study published in 2006 by Cramer et al. indicated that a half of the patients treated with bisfosfonates on a daily bases discontinued treatment after one year of therapy (32). Poor adherence could be the main reason for such early discontinuation of treatment with bisfosfonates (33). Values of BTM are in correlation with adherence (34). Similar to daily bisphosphonates, 5 mg daily dose regime of risedronate could lead to low patients' adherence (33). Delmas et al. showed that the efficacy of risedronate 75 mg orally in two consecutive days a month was similar to daily regimen in all studied skeletal regions (35). For the L region, monthly risedronate regimen with doses 100 mg and 150 mg showed slightly lower, but 200 mg higher efficacy than risedronate 5mg/daily. This study explored efficacy only at L spine (22). One more study presented similar efficacy in L spine of weekly (35 mg and 50 mg) risedronate treatment compared to 5 mg daily regimen (36). Selective estrogen receptor modulators (SERMs) or estrogen agonists/antagonists demonstrated positive effects on both fracture reduction and breast cancer risk reduction (2), but negative effects on endometrial sti- mulation (37, 38). Second class of SERM, arzoxifene, lasofoxifene and bazedoxifene had positive effects on bone formation and a little effect on uterine stimulation (39-41). Published results showed positive effects of arzoxifene on BMD and no significant side effects on uterus and endometrium (27). Different doses of bazedoxifene showed higher percentage change of BMD on L than on thoracic spine. Efficacy of basedoxifene was slightly lower than efficacy of raloxifene. Bazedoxifene have shown similar incidence of adverse events as placebo. Deep vein thrombosis, vasodilatation, leg cramps and breast cysts/fibrocystic breast disease were less common than with raloxifene therapy (28). Fracture risk is one of the most important outcomes of efficacy evaluation. It is necessary for further studies to display accurate information on fracture risks. Limitations Several limitations were noted during the study review: a) only one study presented numerical values of BMD at the beginning and at the end of the study (21). Other studies presented graphical increase of BMD from the baseline values (without specified values) and percent change of BMD at the end of the study. This might lead to conclusion bias: a) only one study that examined efficacy of basedoxifene and arzoxifene was considered in the review b) duration of reviewed studies was different, thus comparing the results could be inadequate; c) although the most of the analyzed studies had as a second aim the analysis of drug safety, in this paper we reviewed only efficacy of the drugs; d) only articles published in English were included in the review. According to this analysis, almost all reviewed drugs, with exception of TPTD, showed similar efficacy at the L skeletal region. The best results at all skeletal sites were achieved with TPTD. Efficacy of all examined drugs was less in hip than in L spine. Taking into account the cost and complications during the treatment of patients with TH fractures, the search for a new potential drugs/way of application need to be continued. The main goal of new treatment should be improved efficacy in all skeletal regions especially in TH region. Also, when considering the efficacy of drugs, it is necessary to consider the costeffectiveness of potential treatments and fracture risk assessment. Table 1. A brief review of basic information and main results of selected clinical studies phase 2 and 3 Authors, year of publication, country [ref] Study design/ drugs to compare, measurements Study population, inclusion criteria N (f): 200, MA (y): 66.10 PSMW (aged up to 80 yr), BMD (L) -4.0T-score -1.8, BMD (FN, TH) -3.5T-score 1.8 N (f): 165, MA (y): 64.06 PSMW (aged 50­81yr), BMD according to WHO criteria At the end of 14yr: L: -2.14 (0.77) TH: -1.42 (0.69) FN: -1.86 (0.67) 1/3R: -1.48 (1.18) L: -3.2 (0.7) TH: -1.6 (0.7) Open-label, single-arm, M: BMD (L, TH, 1/3R, FN), BTM (BSAP, CTX) L: 2.9 TH: 1.1 FN: 1.2 1/3R: 1.0 CTX , BSAP in all measured time points Study period, country and duration of study BMD T-score (SD) baseline or in comparable/plac ebo group Change (%) of BMD vs. comparator, BTM changes Drug/supplements (dose) Miller PD, et al., 2010 (21) Denosumab (60mg every 6 months, sc)/ Calcium (500mg) daily PO, Vitamin D (400IU) daily PO R, PC, positive control / DTC: TPTD 20g SC, Pb-patch M: BMD (L, left TH, FN, left F), BTM (P1NP, CTX, total serum calcium) Cosman F, et al., 2010 (25) NA, USA, 2 years extension of a 4-year study (6 years in total) NA, USA, Argentina, Mexico, 6months Teriparatide (20, 30, 40g 30min wear time daily, TP) Ste-Marie LG, et al., 2009 (22) April 2004 ­ June 2005, international , 6-months Risedronate (100mg; 150mg; 200 mg monthly, PO) / Calcium (1000mg) daily, Vitamin D (400IU) daily R, DB, active-controlled, dose-ranging / DTC: Risedronate 5mg/daily, PO M: BMD, BTM (CTX, NTX, BSAP) N (f): 370, MA (y): 65,74 PSMW (at least 5 yr), age 50 to 85yr, BMI:18-32kg/m2, BMD (L) T- score - 2.0 5 mg/day; 100mg monthly; 150mg monthly; 200 mg monthly; L: -3.11 (0.87) / 3.12 (0.82) / 2.93 (0.81) / 2.98 (0.83) N (f/m): 136 TPTD group (127/9) and 67 placebo group (62/5); MA (y): TPTD group: 69.2; NA Miyauchi A, et al., 2010 (20) NA, Japan, 2 years Teriparatide (20 g/day, sc) / Calcium (610mg), Vitamin D (400IU) daily PO R, DB, PC, open-label / Administration: The 1st 12 months: case group used TPTD and control L: 2.96** ( TPTD-P 20g) L: 3.47** (TPTD-P 30g) L: 4.97** (TPTD-P 40g) L: 3.55** (TPTD-Inj 20g) TH:1.33* (TPTD-P 40g) TH: 0.09 (TPTD-Inj 20g) No stat. sign. diff. for FN. F Pb-patch P1NP, CTX significantly different vs. Pb-patch group for all treatment groups L: 3.05*** (5 mg/day) L: 2.10*** (100mg monthly) L: 2.99*** (150mg monthly) L: 3.38*** (200 mg monthly) C: baseline BTM sign. from bv. At the end of 12M;18M;24M L: 10,23**; 12,38; 13,96 used Pb; the 2nd 12 months: all subjects used TPTD M: BMD (L, FN, TH), BTM (P1NP, BSAP, CTX), new fractures TH: 2,66**; 3,23; 3,69 FN: 2,24; 2,92; 3,25 C: Pb P1NP, CTX sign. from bv. BSAP sign. from bv. L: -3.40 ± 0.87 TH: - 1.99 ± 0.57 FN: -2.49 ± 0.55 75mg/2 days a month / 5mg/day L:-3.16 (0.54) / 3.17 (0.56) TH: -1.91 (0.77) / -1.86 (0.78) FN: -2.09 (0.61) / -2.05 (0.64) Risedronate: L: -1.81 FN: -1.29 Placebo group: 70.4 PSMW (5 yr), man and women 55 yr: BMD (L2­ L4)<80% of YAM + min. one vertebral fracture; BMD (L2­ L4)<70% + age65; BMD (L2­L4)<65% + age55 N (f): 41 TPTD and 41 placebo group, MA (y): 62.0PSMW (3 yr), age 45 to 75yr, T-score (L, FN, TH) -2.5 N (f): 1229, MA (y): 64.65 PSMW (5 yr), age 50 yr, BMD according to WHO criteria Teriparatide: L: 11.30 ** TH: 8.12 FN: 4.87 C: baseline BTM, BRM from bv. 75mg/2 days a month / 5mg/day L: 3.4*** / 3.6*** TH: 2.1 / 1.9 FN: 1.6 / 1.2 Trh: 3.0 / 3.0 C: baseline Sethi BK, et al., 2008 (23) 12.2005 ­ 08. 2007, India, 6months Teriparatide (20 g/day, sc) / Calcium (1000mg), Vitamin D (500IU) daily PO Delmas PD, et al. 2008 (26) NA, international , 1 year Risedronatee (75mg on 2 consecutive days a month, PO)/ Calcium (1000mg), Vitamin D (400800IU) daily PO R,DB, PC, parallel-group /DTC: Pb, M: BMD (L, PF); BTM (NTX, BSAP) R, DB, double-dummy study / DTC: Alendronate (Fosamax) 70mg once weekly PO, M: BMD (L, PF, FN, D1/3R), BTM (P1NP, CTX) R, multicentre, prospective, open-label, controlled M: BMD and BMC (L, TH, FN); BTM (BSAP, OC, DPD) R, DB, active-controlled, parallel-group / DTC: Risedronate 5mg/day, PO, M: BMD (L, TH, FN, Trh), BTM (NTX, BSAP) Välimäki MJ, et al., 2007 (42) NA, international , 2 years Risedronate (5mg/day, PO) / Calcium (1000mg), Vitamin D (400IU) daily PO Kendler DL, et al., 2010 (24) 10. 2006 ­ 03. 2008, international 1 year Denosumab (60mg once every 6 months, sc) / Calcium (1000mg/d) Vitamin D (400IU) daily PO N (f): 171, MA (y): 65.9 Healthy, ambulatory, PSMW (5 yr), BMD (L) -2.5 T-score -1.0; BMD (TH) T-score -1, or the presence of 1 risk factor for osteoporosis N (f): 504, MA (y): 67.6 PSMW, age 55yr, BMD Tscore -2.0 or less; BMD Tscore -4.0 who had been receiving alendronate for at least 6 months Denosumab / Alendronate: L: - 2.64 (0.75) / -2.62 (0.79) TH: -1.79 (0.82) / -1.81 (0.74) Bolognese M et al., 2009 (27) NA, NA, 2 years Arzoxifene (20 mg/day, PO) / Calcium (500mg/d) Multicenter, R, placebocontrolled / DTC: Pb, M: BMD (L, TH), BTM (P1NP, CTX), mammogram, gynecological procedures N (f): 331, MA (y): 54,69 PSMW (at least 2 yr), age 45 60yr, BMD (L, FN) -2.5 Tscore 0; no vertebral fracture Arzoxifene / Pb L: 0.95 ± 0.12 / 0.96 ± 0.12 TH: 0.886 ± 0.09 / 0.894 ± 0.10 Risedronate: L: 4.49* FN: 2.04* C: baseline BTM sign. from bv. and Pb Denosumab / Alendronate: L: 3.03 / 1.85 TH: 1.90/ 1.05 C: baseline CTX sign. at all measurement points between treatment groups (higher decrease in denosumab group) Arzoxifene / Pb L: 2.92** TH: 2.19** C: Pb Silverman SL, et al., 2008 (28) NA, international 3 years Bazedoxifene (20mg, 40 mg daily, PO) / Calcium (1200mg/d), Vitamin D (400-800IU) daily PO R, DB, placebo- and active-controlled / DTC: Raloxifene 60mg/day PO, Pb, M: RM of vertebral fractures (T4­L4); BMD (L, TH, FN), BTM (CTX, OC) N (f): 7492, MA (y): 66.4 PSMW (at least 2 yr), age 55 85 yr, osteoporosis; BMD (L, FN) -4.0T-score -2.5, no prevalent vertebral fracture Bazedoxifene 20mg/40mg/Ralo xifene 60mg/Pb L: -2.4 (1.2) / 2.4 (1.2) / -2.4 (1.2) / -2.4 (1.2) FN: -1.7 (0.9) / 1.7 (0.9) /-1.7 (0.9) / -1,8 (0,9) Bazedoxifene 20mg/40mg/Raloxifene 60mg/Pb L: 2.21** /2.38** / 2.96** TH: 0.27 ** / 0.50** / 0.90** C: Pb OC, CTX sign. from Pb R ­ Randomized Pb - placebo C - Placebo - controlled NA ­ not available (not presented in article) DB - Double-blind * Significant difference at the level 0.05 DTC - Drugs to compare ** Significant difference at the level 0.001 N ­ Number *** Significant difference is noted but the level is not specified f- female Significance level not specified m- male Not significant difference MA - Mean age M - Measurements BTM - Bone Turnover Markers BMC ­ Bone Mineral Content P1NP - Terminal propeptide of type I procollagen CTX ­ Serum C-telopeptide type I OC ­ Serum osteocalcin NTX ­ Urinary N-telopeptide fragment of type I collagen BSAP ­ Bone specific alkaline phosphatase DPD ­ Urinary deoxypyridinoline TP ­ Transdermal Patch PO ­ Per Os Sc ­ Sub Cutaneus RM: radiographycally measurement PSMW- Post-menopausal women Bv. ­ Baseline value C ­ Comparator F - forearm PF - proximal femur TH - total hip Trc - trochanter L - lumbar spine 1/3R - one third radius WHO Criteria: BMD (L, FN or TH) T-score - 2.5, BMD (L) T-score -1; or BMD (L, FN or TH) T-score - 2.0 with a prevalent vertebral fracture CG ­ control group http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Facultatis Medicae Naissensis de Gruyter

New drugs for osteoporosis therapy: a review of the clinical trials phase 2 and 3

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Abstract

to identify if a study meets the specified criteria. For the articles unavailable in full length the corresponding authors were contacted. All collected articles were included into further analysis. Selection of studies Only articles that published the results of the CTP 2 and CTP3 were included in the review process. Studies comparing an intervention to placebo or to another intervention were eligible for inclusion. The studies were selected if they met the endpoints, measurement of bone mineral density (BMD) and/or bone turnover markers (BTM). The articles which did not measure BMD and/or percentage change of BMD compared to baseline values as an endpoint were excluded. Also, studies that examined drug efficacy in patients with secondary osteoporosis (breast, ovarian or prostate cancer) were excluded. There were no limits regarding the patient's gender, duration or type of the study, and pharmacological classification of drug for osteoporosis treatment. Types of outcome measures Studies that reported values of BMD and BTM were considered for this review. Studies that measured BMD by Dual-energy x-ray absorptiometry (DXA) on the total hip (TH), femoral neck (FN), lumbar spine (region L1-L4) (L), and forearm (distal radius) and presented BMD change in g/cm2 or as a percentage change (a difference between the values of BMD at the end of the study versus baseline value) were included. Bone turnover is associated with the low BMD and high fracture risk (5). BMD changes in a short-term period can be well predicted by changes of biochemical markers (17). Changes in bone metabolism can be faster assessed by measuring of BTM than BMD. Therefore, early assessment of efficacy of osteoporosis therapy should be followed by the values of BTM (18). Two groups of well-known BTM are used: bone formation and bone resorption markers. Frequently used biochemical bone formation markers are specific for collagen formation (osteocalcin (OC), bone-specific alkaline phosphatise (BSAP) and amino-terminal propeptide of type 1 collagen (PI NP)). Mostly used resorption markers are deoxypyrolidinoline, amino- and carboxy­terminal cross-linked telopeptides of type 1 collagen (NTX, CTX) (19). BTM can be measured in serum (BSAP, OC, CTX, PINP) or urine (NTX, Urinary deoxypyridinoline (DPD)) according to the reference methods. Efficacy evaluation Efficacy of medicines for osteoporosis treatment was examined as the percentage change of BMD or/and change in BTM (decrease during the therapy with antiresorptive agents or increase during the therapy with anabolic agents). The fracture risk, if reported, was also examined in all selected articles. Figure 1. Article selection In the analyzed articles, all five drugs increased L BMD in the range from 2.1% (risedronate 100 mg per os, once monthly during 6 months) (22) to 11.3% (TPTD 20 g daily subcutaneous injection during 6 months) (Table 1) (20, 22, 23). Two studies demonstrated that after one-year treatment with denosumab (60mg subcutaneous (sc) injection every 6 months) the increase of BMD was the highest in L spine in comparison with other skeletal sites (21, 24). One-year treatment study conducted by Kendler et al. showed that the improvement of BMD after denosumab treatment was significantly higher (3%, p <0.05) at the L site, as well as at the TH site (1,9%, p<0.001) in comparison to alentronate (70 mg once weekly) (24). Miller et al. showed a constant increase of the L BMD with the same doses of denosumab therapy during the two-year extension study (BMD T-score - 2,14 in the beginning and -1,55 in the end of the study, without specified level of significance) (21). All three articles that described TPTD efficacy showed significant increase only for L spine (20, 23, 25). As TPTD is a peptide hormone, it cannot be given orally and currently can only be administered as a daily sc injection. A new transdermal administration of TPTD made its application more convenient. Increase of TH BMD was significant (p<0.05) after 6-month administration of 40 g daily TPTD transdermal-patch (1.33% change) in comparison to placebo-patch (-0.63% change), and 20 g daily TPTD sc injection (0.09% change). Other daily TPTD transdermal-patch doses (20 g and 30 g), did not show significant improvement of BMD at TH region, unlike L region where all examined TPTD transdermal-patch doses showed significant improvement (~3% for dose of 20 g; ~3.5% for dose of 30 g; ~5% for RESULTS After the initial search of the PubMed and Scopus databases, 57 articles were identified. Forty-two articles were excluded by the title after abstract review or because they did not meet the required criteria. Nine articles were not available in full text format, however, four of them were obtained from the corresponding authors. The final review included 10 articles (Figure 1). In selected articles, all studies recruited postmenopausal women for the analysis except one (20). Half of the articles published the results of multicenter international clinical trials. Measurement of BMD on L spine was performed in all the studies, and in some of them BMD was additionally measured on the forearm (F), proximal femur (PF), TH and/or trochanter (Trc). In all the studies, patients were taking additional supplements of calcium and/or vitamin D. Selected articles examined efficacy of five different drugs: denosumab, TPTD, arzoxifene, risedronate and bazedoxifene (Table 1). Value of BMD at the end of the study versus baseline value is a useful indicator of medication efficacy, but only one article presented both values. All other studies showed their results as BMD percentage change without specifying what was the BMD value at the end of the study (21). Studies' aims, main results, baseline BMD and percentage of its change at the end of the study were presented in Table 1. dose of 40 g, p<0.001) in comparison to baseline values and placebo (25). Another study showed better results of daily sc. injection form of TPTD in TH region. Increase of BMD at the TH (2.66%, p<0.001) was statistically significant after first 12 months of therapy in comparison to baseline. Follow-up therapy (from 12 to 24 months), showed continuous but not statistically significant increase of TH BMD (20). New monthly oral therapeutic regiment of risedronate was also examined as a more convenient way of application. Doses of 100, 150 or 200mg once a month showed efficacy similar to standard 5 mg daily dose after a 6-month therapy. Percentage changes of L BMD was not significantly different between applications of risedronate daily regimen (~3%) and monthly regimens: ~2% (100 mg monthly); ~3% (150 mg monthly); ~3,4% (200 mg monthly) (22). Investigation of new therapeutic regimen of risedonate therapy of 75 mg at two consecutive days a month showed similar efficacy (L BMD+3,4%) to standard daily dose (L BMD+3,6%) after one year of application (26). Arzoxifene (20 mg/daily, per os, during two years of application) showed a significant increase of BMD at the level of p<0.001 at the L and TH region (2.92%, 2.19%, p<0.001) compared with placebo (27). Bazedoxifene (20 mg/daily and 40 mg/daily, per os, during 3 years of application) showed a similar efficacy as raloxifene 60mg compared with placebo (percentage change in L spine was 2.21%, 2.38%, 2.96, p <0.001 respectively; percentage change in TH was 0.27 %, 0.50%, 0.90, p<0.001, respectively) (27, 28). From 10 selected articles only one reported data about fracture risk. Silverman et al. have reported that bazedoxifene (20mg, 40mg daily) and raloxifene significantly reduced the risk of new vertebral fractures after 36 months of therapy compared to placebo (42%, 37%, 42%, respectively) (28). DISCUSSION This review presented efficacy of osteoporosis drugs that are currently in clinical trials phase 2 and 3. Beside efficacy of new drugs, some of the studies tested new dosing regimens, or new ways of application of existing drugs. All the reviewed studies showed that the examined drugs increased more BMD in L spine region than in the hip region. Denosumab has high specificity and affinity for RANKL (6, 11, 29), and pharmacokinetic properties that allow its application once per every six months (11). This dosing regimen enables better adherence. Denosumab therapy (60 mg sc every 6 months) showed a modest efficacy. After six years of therapy with denosumab, the improvement in BMD was about 3% in L spine and 1% in TH region (21). In the study conducted by McClung et al. denosumab applied in different therapeutic regimens (6, 14 or 30 mg sc every three months or 14, 60, 100, or 210 mg sc every six months) after 12 months of therapy showed a similar efficacy (L spine: 3.0-6.7%, TH: 1.9-3.6%) (30). The study conducted by Kendler et al. showed that after switching therapy from alendronate (70 mg weekly, per os) to denosumab (60 mg/6 months, sc), increase of BMD in L and TH was significantly (p<0.0001) higher during the 12-month therapy (BMD % change in L spine: 1.85%, 3.03%, respectively; and TH region: 1.05%, 1.90%, respectively). After switching, the adherence was better with 60mg/6 months denosumab therapy. The interesting fact was that BTM at the end of the study reached almost the baseline value in subjects continuing on alendronate but not in the denosumab group (24). Study conducted by Miller et al. examined effects of denosumab discontinuation after a two-year treatment (210 mg/6months, sc). Discontinuation period lasted one year. At the end of that period BMD decreased by 6.6% at the L spine and 5.3% at the TH. After discontinuation period, retreatment was continued with denosumab sc 60 mg/6 months dose for a period of one year. At the end of retreatment period, BMD was increased by 9% in L spine and 3.9% in the total hip compared to the baseline values (31). TPTD daily sc application, showed the best efficacy in BMD improvement in all measured skeletal regions (LS, TH and FN) in comparison to all examined drugs in this review (20, 25). Study conducted by Miyauchi et al. demonstrated that treatment with TPTD 20 g/day sc. inj constantly improved BMD during the two-year study period compared to baseline values (20). TPTD daily sc application was uncomfortable, thus a new formulation of TPTD as transdermal patches was developed. The best results were achieved with 40 g TPTD patch at the L spine (improvement about 5%) (25). Review study published in 2006 by Cramer et al. indicated that a half of the patients treated with bisfosfonates on a daily bases discontinued treatment after one year of therapy (32). Poor adherence could be the main reason for such early discontinuation of treatment with bisfosfonates (33). Values of BTM are in correlation with adherence (34). Similar to daily bisphosphonates, 5 mg daily dose regime of risedronate could lead to low patients' adherence (33). Delmas et al. showed that the efficacy of risedronate 75 mg orally in two consecutive days a month was similar to daily regimen in all studied skeletal regions (35). For the L region, monthly risedronate regimen with doses 100 mg and 150 mg showed slightly lower, but 200 mg higher efficacy than risedronate 5mg/daily. This study explored efficacy only at L spine (22). One more study presented similar efficacy in L spine of weekly (35 mg and 50 mg) risedronate treatment compared to 5 mg daily regimen (36). Selective estrogen receptor modulators (SERMs) or estrogen agonists/antagonists demonstrated positive effects on both fracture reduction and breast cancer risk reduction (2), but negative effects on endometrial sti- mulation (37, 38). Second class of SERM, arzoxifene, lasofoxifene and bazedoxifene had positive effects on bone formation and a little effect on uterine stimulation (39-41). Published results showed positive effects of arzoxifene on BMD and no significant side effects on uterus and endometrium (27). Different doses of bazedoxifene showed higher percentage change of BMD on L than on thoracic spine. Efficacy of basedoxifene was slightly lower than efficacy of raloxifene. Bazedoxifene have shown similar incidence of adverse events as placebo. Deep vein thrombosis, vasodilatation, leg cramps and breast cysts/fibrocystic breast disease were less common than with raloxifene therapy (28). Fracture risk is one of the most important outcomes of efficacy evaluation. It is necessary for further studies to display accurate information on fracture risks. Limitations Several limitations were noted during the study review: a) only one study presented numerical values of BMD at the beginning and at the end of the study (21). Other studies presented graphical increase of BMD from the baseline values (without specified values) and percent change of BMD at the end of the study. This might lead to conclusion bias: a) only one study that examined efficacy of basedoxifene and arzoxifene was considered in the review b) duration of reviewed studies was different, thus comparing the results could be inadequate; c) although the most of the analyzed studies had as a second aim the analysis of drug safety, in this paper we reviewed only efficacy of the drugs; d) only articles published in English were included in the review. According to this analysis, almost all reviewed drugs, with exception of TPTD, showed similar efficacy at the L skeletal region. The best results at all skeletal sites were achieved with TPTD. Efficacy of all examined drugs was less in hip than in L spine. Taking into account the cost and complications during the treatment of patients with TH fractures, the search for a new potential drugs/way of application need to be continued. The main goal of new treatment should be improved efficacy in all skeletal regions especially in TH region. Also, when considering the efficacy of drugs, it is necessary to consider the costeffectiveness of potential treatments and fracture risk assessment. Table 1. A brief review of basic information and main results of selected clinical studies phase 2 and 3 Authors, year of publication, country [ref] Study design/ drugs to compare, measurements Study population, inclusion criteria N (f): 200, MA (y): 66.10 PSMW (aged up to 80 yr), BMD (L) -4.0T-score -1.8, BMD (FN, TH) -3.5T-score 1.8 N (f): 165, MA (y): 64.06 PSMW (aged 50­81yr), BMD according to WHO criteria At the end of 14yr: L: -2.14 (0.77) TH: -1.42 (0.69) FN: -1.86 (0.67) 1/3R: -1.48 (1.18) L: -3.2 (0.7) TH: -1.6 (0.7) Open-label, single-arm, M: BMD (L, TH, 1/3R, FN), BTM (BSAP, CTX) L: 2.9 TH: 1.1 FN: 1.2 1/3R: 1.0 CTX , BSAP in all measured time points Study period, country and duration of study BMD T-score (SD) baseline or in comparable/plac ebo group Change (%) of BMD vs. comparator, BTM changes Drug/supplements (dose) Miller PD, et al., 2010 (21) Denosumab (60mg every 6 months, sc)/ Calcium (500mg) daily PO, Vitamin D (400IU) daily PO R, PC, positive control / DTC: TPTD 20g SC, Pb-patch M: BMD (L, left TH, FN, left F), BTM (P1NP, CTX, total serum calcium) Cosman F, et al., 2010 (25) NA, USA, 2 years extension of a 4-year study (6 years in total) NA, USA, Argentina, Mexico, 6months Teriparatide (20, 30, 40g 30min wear time daily, TP) Ste-Marie LG, et al., 2009 (22) April 2004 ­ June 2005, international , 6-months Risedronate (100mg; 150mg; 200 mg monthly, PO) / Calcium (1000mg) daily, Vitamin D (400IU) daily R, DB, active-controlled, dose-ranging / DTC: Risedronate 5mg/daily, PO M: BMD, BTM (CTX, NTX, BSAP) N (f): 370, MA (y): 65,74 PSMW (at least 5 yr), age 50 to 85yr, BMI:18-32kg/m2, BMD (L) T- score - 2.0 5 mg/day; 100mg monthly; 150mg monthly; 200 mg monthly; L: -3.11 (0.87) / 3.12 (0.82) / 2.93 (0.81) / 2.98 (0.83) N (f/m): 136 TPTD group (127/9) and 67 placebo group (62/5); MA (y): TPTD group: 69.2; NA Miyauchi A, et al., 2010 (20) NA, Japan, 2 years Teriparatide (20 g/day, sc) / Calcium (610mg), Vitamin D (400IU) daily PO R, DB, PC, open-label / Administration: The 1st 12 months: case group used TPTD and control L: 2.96** ( TPTD-P 20g) L: 3.47** (TPTD-P 30g) L: 4.97** (TPTD-P 40g) L: 3.55** (TPTD-Inj 20g) TH:1.33* (TPTD-P 40g) TH: 0.09 (TPTD-Inj 20g) No stat. sign. diff. for FN. F Pb-patch P1NP, CTX significantly different vs. Pb-patch group for all treatment groups L: 3.05*** (5 mg/day) L: 2.10*** (100mg monthly) L: 2.99*** (150mg monthly) L: 3.38*** (200 mg monthly) C: baseline BTM sign. from bv. At the end of 12M;18M;24M L: 10,23**; 12,38; 13,96 used Pb; the 2nd 12 months: all subjects used TPTD M: BMD (L, FN, TH), BTM (P1NP, BSAP, CTX), new fractures TH: 2,66**; 3,23; 3,69 FN: 2,24; 2,92; 3,25 C: Pb P1NP, CTX sign. from bv. BSAP sign. from bv. L: -3.40 ± 0.87 TH: - 1.99 ± 0.57 FN: -2.49 ± 0.55 75mg/2 days a month / 5mg/day L:-3.16 (0.54) / 3.17 (0.56) TH: -1.91 (0.77) / -1.86 (0.78) FN: -2.09 (0.61) / -2.05 (0.64) Risedronate: L: -1.81 FN: -1.29 Placebo group: 70.4 PSMW (5 yr), man and women 55 yr: BMD (L2­ L4)<80% of YAM + min. one vertebral fracture; BMD (L2­ L4)<70% + age65; BMD (L2­L4)<65% + age55 N (f): 41 TPTD and 41 placebo group, MA (y): 62.0PSMW (3 yr), age 45 to 75yr, T-score (L, FN, TH) -2.5 N (f): 1229, MA (y): 64.65 PSMW (5 yr), age 50 yr, BMD according to WHO criteria Teriparatide: L: 11.30 ** TH: 8.12 FN: 4.87 C: baseline BTM, BRM from bv. 75mg/2 days a month / 5mg/day L: 3.4*** / 3.6*** TH: 2.1 / 1.9 FN: 1.6 / 1.2 Trh: 3.0 / 3.0 C: baseline Sethi BK, et al., 2008 (23) 12.2005 ­ 08. 2007, India, 6months Teriparatide (20 g/day, sc) / Calcium (1000mg), Vitamin D (500IU) daily PO Delmas PD, et al. 2008 (26) NA, international , 1 year Risedronatee (75mg on 2 consecutive days a month, PO)/ Calcium (1000mg), Vitamin D (400800IU) daily PO R,DB, PC, parallel-group /DTC: Pb, M: BMD (L, PF); BTM (NTX, BSAP) R, DB, double-dummy study / DTC: Alendronate (Fosamax) 70mg once weekly PO, M: BMD (L, PF, FN, D1/3R), BTM (P1NP, CTX) R, multicentre, prospective, open-label, controlled M: BMD and BMC (L, TH, FN); BTM (BSAP, OC, DPD) R, DB, active-controlled, parallel-group / DTC: Risedronate 5mg/day, PO, M: BMD (L, TH, FN, Trh), BTM (NTX, BSAP) Välimäki MJ, et al., 2007 (42) NA, international , 2 years Risedronate (5mg/day, PO) / Calcium (1000mg), Vitamin D (400IU) daily PO Kendler DL, et al., 2010 (24) 10. 2006 ­ 03. 2008, international 1 year Denosumab (60mg once every 6 months, sc) / Calcium (1000mg/d) Vitamin D (400IU) daily PO N (f): 171, MA (y): 65.9 Healthy, ambulatory, PSMW (5 yr), BMD (L) -2.5 T-score -1.0; BMD (TH) T-score -1, or the presence of 1 risk factor for osteoporosis N (f): 504, MA (y): 67.6 PSMW, age 55yr, BMD Tscore -2.0 or less; BMD Tscore -4.0 who had been receiving alendronate for at least 6 months Denosumab / Alendronate: L: - 2.64 (0.75) / -2.62 (0.79) TH: -1.79 (0.82) / -1.81 (0.74) Bolognese M et al., 2009 (27) NA, NA, 2 years Arzoxifene (20 mg/day, PO) / Calcium (500mg/d) Multicenter, R, placebocontrolled / DTC: Pb, M: BMD (L, TH), BTM (P1NP, CTX), mammogram, gynecological procedures N (f): 331, MA (y): 54,69 PSMW (at least 2 yr), age 45 60yr, BMD (L, FN) -2.5 Tscore 0; no vertebral fracture Arzoxifene / Pb L: 0.95 ± 0.12 / 0.96 ± 0.12 TH: 0.886 ± 0.09 / 0.894 ± 0.10 Risedronate: L: 4.49* FN: 2.04* C: baseline BTM sign. from bv. and Pb Denosumab / Alendronate: L: 3.03 / 1.85 TH: 1.90/ 1.05 C: baseline CTX sign. at all measurement points between treatment groups (higher decrease in denosumab group) Arzoxifene / Pb L: 2.92** TH: 2.19** C: Pb Silverman SL, et al., 2008 (28) NA, international 3 years Bazedoxifene (20mg, 40 mg daily, PO) / Calcium (1200mg/d), Vitamin D (400-800IU) daily PO R, DB, placebo- and active-controlled / DTC: Raloxifene 60mg/day PO, Pb, M: RM of vertebral fractures (T4­L4); BMD (L, TH, FN), BTM (CTX, OC) N (f): 7492, MA (y): 66.4 PSMW (at least 2 yr), age 55 85 yr, osteoporosis; BMD (L, FN) -4.0T-score -2.5, no prevalent vertebral fracture Bazedoxifene 20mg/40mg/Ralo xifene 60mg/Pb L: -2.4 (1.2) / 2.4 (1.2) / -2.4 (1.2) / -2.4 (1.2) FN: -1.7 (0.9) / 1.7 (0.9) /-1.7 (0.9) / -1,8 (0,9) Bazedoxifene 20mg/40mg/Raloxifene 60mg/Pb L: 2.21** /2.38** / 2.96** TH: 0.27 ** / 0.50** / 0.90** C: Pb OC, CTX sign. from Pb R ­ Randomized Pb - placebo C - Placebo - controlled NA ­ not available (not presented in article) DB - Double-blind * Significant difference at the level 0.05 DTC - Drugs to compare ** Significant difference at the level 0.001 N ­ Number *** Significant difference is noted but the level is not specified f- female Significance level not specified m- male Not significant difference MA - Mean age M - Measurements BTM - Bone Turnover Markers BMC ­ Bone Mineral Content P1NP - Terminal propeptide of type I procollagen CTX ­ Serum C-telopeptide type I OC ­ Serum osteocalcin NTX ­ Urinary N-telopeptide fragment of type I collagen BSAP ­ Bone specific alkaline phosphatase DPD ­ Urinary deoxypyridinoline TP ­ Transdermal Patch PO ­ Per Os Sc ­ Sub Cutaneus RM: radiographycally measurement PSMW- Post-menopausal women Bv. ­ Baseline value C ­ Comparator F - forearm PF - proximal femur TH - total hip Trc - trochanter L - lumbar spine 1/3R - one third radius WHO Criteria: BMD (L, FN or TH) T-score - 2.5, BMD (L) T-score -1; or BMD (L, FN or TH) T-score - 2.0 with a prevalent vertebral fracture CG ­ control group

Journal

Acta Facultatis Medicae Naissensis – de Gruyter

Published: Mar 1, 2014

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