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Keywords:

  • BMD;
  • BONE TURNOVER;
  • CATHEPSIN K;
  • ODANACATIB;
  • OSTEOPOROSIS

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Odanacatib (ODN) is a selective inhibitor of the collagenase cathepsin K that is highly expressed by osteoclasts. In this 2-year, phase 2, dose-ranging trial, postmenopausal women with bone mineral density (BMD) T-scores −2.0 to −3.5 at spine or hip were randomized to weekly placebo or ODN 3, 10, 25, or 50 mg plus vitamin D3 and calcium. Prespecified trial-extensions continued through 5 years. In year 3, all women were re-randomized to ODN 50 mg or placebo. For years 4 and 5, women who received placebo or ODN 3 mg in years 1 and 2 and placebo in year 3 received ODN 50 mg; others continued year 3 treatments. Endpoints included lumbar spine (primary), hip, 1/3 radius, and total body BMD; markers of bone metabolism; and safety. Women in the year 4 to 5 extension receiving placebo (n = 41) or ODN 50 mg (n = 100) had similar baseline characteristics. For women who received ODN (10–50 mg) for 5 years, spine and hip BMD increased over time. With ODN 50 mg continually for 5 years (n = 13), mean lumbar spine BMD percent change from baseline (95% confidence interval [CI]) was 11.9% (7.2% to 16.5%) versus −0.4% (−3.1% to 2.3%) for women who were switched from ODN 50 mg to placebo after 2 years (n = 14). In pooled results of women receiving continuous ODN (10–50 mg, n = 26–29), year 5 geometric mean percent changes from baseline in bone resorption markers cross-linked N-telopeptide of type I collagen (NTX)/creatinine and cross-linked C-telopeptide (CTX) were approximately −55%, but near baseline for bone formation markers bone-specific alkaline phosphatase (BSAP) and amino-terminal propeptide of type I procollagen (P1NP). In women switched from ODN 10 to 50 mg to placebo after 2 years (n = 25), bone turnover markers were near baseline. In summary, women receiving combinations of ODN (10–50 mg) for 5 years had gains in spine and hip BMD and showed larger reductions in bone resorption than bone formation markers. Discontinuation of ODN resulted in reversal of treatment effects. Treatment with ODN for up to 5 years was generally well-tolerated. © 2012 American Society for Bone and Mineral Research.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Osteoporotic fractures impose a large burden on individuals and society, and the number of fractures is expected to increase with the aging of the population.1–3 Loss of bone mass in postmenopausal osteoporosis occurs because bone resorption exceeds bone formation. Potent antiresorptive agents, including the bisphosphonates, and more recently the anti–receptor activator of NF-κB ligand (anti-RANKL) antibody denosumab, are commonly used for osteoporosis treatment. By inhibiting the overall bone turnover process, these drugs preserve and increase bone mass. Through different mechanisms—inhibition of osteoclast function and, under some circumstances, promotion of osteoclast apoptosis for the bisphosphonates4–6 and inhibition of osteoclast development and differentiation for denosumab6, 7—these agents reduce osteoclast number on the bone surface and reduce bone resorption. Because osteoclasts are involved in the signaling process with osteoblasts, reduction in the number of osteoclasts may be a factor in the reduction of bone formation associated with these antiresorptive agents.6–10

Odanacatib (ODN) is a selective inhibitor of the cysteine protease cathepsin K that is expressed predominantly in osteoclasts and degrades the collagen matrix components of bone. ODN, currently in phase 3 development for the treatment of osteoporosis, appears to reduce bone resorption while preserving bone formation in postmenopausal women.11, 12 By dynamic histomorphometric analysis of ovariectomized rhesus monkeys, the effect of odanacatib was seen to vary depending on the bone type.13–15 At the femoral neck and proximal femur, for example, ODN reduced trabecular and intracortical bone formation like other antiresorptives, but preserved endocortical bone formation and stimulated periosteal bone formation.14 An increase in periosteal bone formation was also seen in nonhuman primates with another cathepsin K inhibitor, balicatib.16 ODN, unlike conventional antiresorptives, inhibits osteoclast digestion of the collagenous bone matrix but does not reduce osteoclast number.17 Preservation of osteoclast signaling may account for the finding that bone formation is less affected by treatment with ODN than by treatment with conventional antiresorptives.

ODN was studied in a phase 2 dose-ranging trial in postmenopausal osteoporotic women with low bone mass. Findings from the first 2 years of the study, which represented the dose-ranging portion of the study, have been reported.11 Results from the initial 2 years showed significant dose-dependent increases in spine and hip bone mineral density (BMD) in women receiving 10, 25, or 50 mg of ODN once weekly and significant decreases in biochemical markers of bone resorption, compared to placebo. Initially, biochemical markers of bone formation were also reduced, but to a lesser degree than markers of bone resorption. Bone formation markers returned toward baseline levels by the second year of the study.11

Prespecified trial extensions have added 3 years to the initial 2-year trial. The objectives of the extension studies were to examine the long-term effects of ODN treatment on efficacy and safety, and the resolution of effect upon treatment discontinuation. In the first extension study (the third year of the trial), in women originally treated with 10, 25, or 50 mg of ODN and re-randomized to ODN 50 mg, BMD at spine and hip continued to increase, and biochemical markers of bone resorption remained reduced. However, levels of bone formation biomarkers were near baseline.12 In women who were re-randomized to discontinue ODN treatment, BMD levels returned toward baseline. Following discontinuation of therapy, bone resorption and formation biomarkers showed an initial rapid but transient increase to above baseline, but then decreased toward baseline. Results for the second extension (years 4 and 5 of the trial) are presented here, providing a demonstration of the long-term effects of ODN in postmenopausal women with low BMD.

Subjects and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Study design

A 2-year, randomized, double-blind, multicenter, dose-finding study of postmenopausal women with low BMD (protocol 004) was extended for an additional 3 years (Fig. 1). For the first 2 years (the initial study), participants were randomized to oral weekly ODN, taken without respect to food intake, at 3 mg, 10 mg, 25 mg, 50 mg, or placebo, using a computer-generated randomized allocation schedule. For year 3, women were re-randomized to receive ODN 50 mg or placebo. For years 4 to 5, women receiving ODN 3 mg or placebo in years 1 and 2 were switched to ODN 50 mg. All other treatment groups continued their year 3 regimen. All participants received weekly vitamin D3 5600 IU, and those with calcium intake <1000 mg/day also received calcium (500 mg elemental calcium) daily. Investigators, participants, and those responsible for participant assessments remained blinded throughout the 5 years of the trial. The study was conducted in accordance with principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. Detailed design and results of years 1 and 211 and year 312 of the study have been published.

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Figure 1. Study design.

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Participants

Women enrolled in the initial 2-year study were required to be postmenopausal (≥5 years after cessation of menses or bilateral oophorectomy), aged 45 to 85 years, with BMD T-scores ≤ −2.0 at the lumbar spine, femoral neck, trochanter, or total hip but not < −3.5 at any site. Participants were in general good health with no history of fragility fracture since menopause, as described in Bone and colleagues.11 All participants who completed year 3 were eligible to enroll in the year 4 to 5 extension except those who had used the following medications during the prior 6 months: any oral bisphosphonate, estrogen ± progestin, selective estrogen receptor modulators (SERM), tibolone, aromatase inhibitors, or glucocorticoids (at doses equivalent to daily oral prednisone ≥ 5 mg). Women were also excluded if they had used intravenous bisphosphonates at any time, had active parathyroid disease or secondary hyperparathyroidism, or had hypercalcemia. Women who experienced a hip, spine, or other fragility fracture during years 1 to 3 were given the option of taking another osteoporosis therapy or to continue to receive blinded study therapy. Informed consent was obtained from study participants at the initiation of the study, and again at the beginning of each extension study (year 3 and year 4, see Fig. 1 for the numbers of study participants at each stage).

Assessments

Details of study procedures have been described.11, 12 Briefly, BMD was measured by dual-energy X-ray absorptiometry (DXA) at the hip (total hip, femoral neck, and trochanter), lumbar spine, total body, and 1/3 radius. DXA scans were evaluated centrally. A central laboratory (Synarc, Lyon, France) performed the bone biochemical measurements, including those for urinary N-telopeptides of type I collagen corrected for creatinine (uNTX/Cr by the VITROS NTX assay; Ortho Clinical Diagnostics, Raritan, NJ, USA), urinary deoxypyridinolines corrected for creatinine (uDPD/Cr by the Total DPD HPLC assay; Biorad, Hercules, CA, USA), serum C-telopeptides of type 1 collagen (sCTX by the Crosslaps ELISA assay; Immuno Diagnostic Systems [IDS], Fountain Hills, AZ, USA), serum bone-specific alkaline phosphatase (sBSAP by the OSTASE assay; Beckman Coulter, Sharon Hill, PA, USA), serum N-terminal propeptide of type 1 collagen (sP1NP, by the UniQ ELISA assay; IDS), serum cross-linked carboxy-terminal telopeptide of type 1 collagen (s1CTP, by the UniQ ELISA assay; IDS), and serum tartrate-resistant acid phosphatase isoform 5b (sTRAP 5b, by the Bone TRAP assay; IDS). Safety was assessed from physician examinations, laboratory data, and reporting of adverse experiences (AEs).

Statistical methods

No between-treatment group statistical testing was performed for the analysis of the year 4 to 5 extension of this trial. Mean percent changes from baseline are presented. The full analysis set, comprised of women who entered the year 4 to 5 extension and had baseline and at least one on-treatment measurement, was used to evaluate BMD results. Biochemical marker results were analyzed using the per protocol set of women in the year 4 to 5 extension. Safety and tolerability were evaluated in all women treated in the year 4 to 5 extension.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

The initial 2-year, randomized, double-blind phase 2 trial of the cathepsin K inhibitor ODN was extended for an additional 3 years (Fig. 1). No woman received placebo for more than 3 years, and no woman received the lowest dose (3 mg) of ODN for more than 2 years. All women received vitamin D3 as well as calcium, if required, based on daily intake.

Participants

A total of 141 women entered the year 4 to 5 extension of the ODN phase 2 trial, with approximately 71% receiving ODN 50 mg weekly and 29% receiving placebo (Table 1). Approximately 90% of the women entering the year 4 to 5 extension completed year 5, independent of treatment group (Table 1). Women treated with ODN or placebo in the year 4 to 5 extension were similar to each other in their baseline characteristics at study entry (Table 2). These women were also generally similar to the average participant who enrolled at the beginning of the trial, with the exception that the women enrolled in the year 4 to 5 extension had higher BMD at the 1/3 radius (Table 2).

Table 1. Disposition of Women in the Year 4 to 5 Extension of the Trial
 Placebo OW n (%)Odanacatib 50 mg OW n (%)
  1. One woman discontinued the study due to an adverse event 5 months after discontinuing study drug. She is counted here in the disposition table, which counts women who discontinued from the study drug; however, she is not counted in the adverse event listing (Table 5), which counts discontinuations from the study. This participant did not discontinue from the study until after year 5, during an ongoing year 6 to 10 extension of the study.

  2. OW = once weekly.

Entered fourth year41100
Completed fifth year37 (90)92 (92)
Discontinued4 (10)8 (8)
 Clinical adverse event04 (4)
 Lack of efficacy2 (5)1 (1)
 Withdrew consent1 (2)2 (2)
 Participant moved0 (0)1 (1)
 Other1 (2)0 (0)
Table 2. Baseline Characteristics of Women Enrolled in the Year 4 to 5 Extension and of the Initial Participant Population
 Women enrolled in year 4 to 5 extension studyWomen enrolled at the start of the initial 2-year study
CharacteristicsPlacebo OW (n = 41)Odanacatib 50 mg OW (n = 100)Total (n = 141)All treatment groups (n = 399)
  1. OW = once weekly; BMD = bone mineral density; uNTX = urinary N-telopeptides of type I collagen; sCTX = serum C-telopeptides of type 1 collagen; uDPD = urinary deoxypyridinolines; sBSAP = serum bone-specific alkaline phosphatase; sP1NP = serum N-terminal propeptide of type 1 collagen; sTRAP 5b = serum tartrate-resistant acid phosphatase isoform 5b; s1CTP = serum cross-linked carboxy-terminal telopeptide of type 1 collagen.

Age, years, mean ± SD62.8 ± 7.863.2 ± 6.563.1 ± 6.964.2 ± 7.8
Age <65 years, n (%)25 (61)65 (65)90 (64)223 (56)
Age ≥65 years, n (%)16 (39)35 (35)51 (36)176 (44)
Age at last menses, years, mean ± SD48 ± 746 ± 747 ± 747 ± 7
Race, n (%)
 Asian01 (1)1 (0.7)9 (2.3)
 Black1 (2.4)01 (0.7)3 (0.8)
 White29 (71)75 (75)104 (74)308 (77)
 Multiracial11 (27)24 (24)35 (25)77 (19)
 Polynesian00027 (0.5)
BMD T-score, mean ± SD
 Lumbar spine−2.3 ± 0.7−2.3 ± 0.7−2.3 ± 0.7−2.2 ± 0.8
 Total hip−1.5 ± 0.7−1.4 ± 0.8−1.5 ± 0.7−1.6 ± 0.7
 Femoral neck−1.9 ± 0.6−1.7 ± 0.7−1.7 ± 0.7−1.9 ± 0.7
 Trochanter−1.4 ± 0.6−1.1 ± 0.8−1.2 ± 0.8−1.3 ± 0.8
 1/3 Radius−1.6 ± 1.1−2.0 ± 1.2−1.9 ± 1.1−2.7 ± 1.4
 Total body−1.4 ± 0.8−1.5 ± 0.8−1.5 ± 0.8−1.4 ± 0.8
Biochemical markers, mean ± SD
 uNTX (nmol/mmolCr)41.3 ± 19.546.9 ± 21.345.3 ± 20.944.1 ± 21.1
 sCTX (pg/mL)0.5 ± 0.20.6 ± 0.30.6 ± 0.30.6 ± 0.3
 uDPD (pmol/µmol Cr)9.9 ± 3.510.7 ± 3.410.5 ± 3.411.1 ± 4.6
 sBSAP (µg/L)14.4 ± 4.014.7 ± 5.814.6 ± 5.415.1 ± 5.9
 sP1NP (µg/L)49.9 ± 13.252.8 ± 21.252.0 ± 19.251.1 ± 18.7
 sTRAP 5b (IU/L)3.7 ± 1.03.7 ± 0.93.7 ± 0.93.7 ± 0.9
 s1CTP (µg/L)3.2 ± 1.03.4 ± 0.93.3 ± 0.93.5 ± 1.3

BMD

The primary endpoint of the study was change from baseline in lumbar spine BMD. Figure 2 shows BMD percent changes from baseline for women receiving ODN 50 mg weekly for 5 years and women who received that dose for 2 years followed by placebo for the remaining 3 years. The women who received ODN 50 mg weekly for 5 years appeared to have progressive increases in lumbar spine BMD throughout the trial. For those who were switched to placebo after 2 years, BMD returned to baseline or slightly below baseline during the following 3 years (Fig. 2A). At the hip sites (total hip, Fig. 2B; femoral neck, Fig. 2C; and trochanter, Fig. 2D), BMD also continued to increase through the 5 years, though the rate of gain may have been attenuated in years 4 and 5. The effects of discontinuation of ODN on BMD at hip sites were similar to those observed at the lumbar spine; ie, return to baseline or slightly below. No group received placebo for 5 years; therefore, we present BMD data for women who received placebo though year 3 of the trial in Fig. 2.

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Figure 2. Percent change from baseline in bone mineral density.

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Table 3 shows BMD changes from baseline at all sites after 5 years for all treatment groups. Women who received either placebo or ODN 3 mg during the first 2 years of the trial, then switched to ODN 50 mg for the next 3 years, had positive changes from baseline in BMD at the spine and hip, albeit these were lower than women who received higher doses continuously for 5 years (ODN 10 or 25 mg for 2 years, followed by ODN 50 mg for 3 years, or ODN 50 mg continuously for 5 years). BMD measured at the 1/3 radius was maintained near baseline or above in women treated continuously with ODN 50 mg compared with women who switched to placebo after 2 years of treatment with ODN 50 mg. Total body BMD was maintained with continuous ODN treatment (10, 25, or 50 mg), whereas it decreased in women switched to placebo after 2 years of ODN treatment.

Table 3. Mean Percent Changes From Baseline in BMD After 5 Years
Treatment in years 1 to 2Treatment in year 3Treatment in years 4 to 5nLumbar spine % (95% CI)Total hip % (95% CI)Femoral neck % (95% CI)Trochanter % (95% CI)1/3 Radius % (95% CI)Total body % (95% CI)
  1. BMD = bone mineral density; CI = confidence interval.

10 mgPlaceboPlacebo10–110.5 (−3.3 to 4.3)0.3 (−0.9 to 1.5)−1.3 (−3.4 to 0.7)0.9 (−1.4 to 3.1)−3.3 (−6.8 to 0.2)−2.4 (−4.6 to −0.2)
25 mgPlaceboPlacebo130.6 (−1.4 to 2.6)0.5 (−2.0 to 3.0)−0.2 (−1.9 to 1.5)0.4 (−3.8 to 4.6)−2.4 (−4.9 to 0.1)−1.8 (−3.7 to 0.1)
50 mgPlaceboPlacebo13–14−0.4 (−3.1 to 2.3)−1.8 (−3.4 to –0.1)−1.6 (−3.7 to 0.5)−1.0 (−2.7 to 0.6)−4.4 (−7.6 to −1.2)−2.0 (−3.8 to −0.1)
PlaceboPlacebo50 mg136.9 (2.7 to 11.1)1.6 (−1.5 to 4.7)1.8 (−2.3 to 5.8)3.1 (−1.5 to 7.6)−3.6 (−6.6 to −0.7)−0.1 (−1.7 to 1.6)
Placebo50 mg50 mg14–155.4 (2.7 to 8.0)3.7 (1.6 to 5.7)3.1 (0.5 to 5.6)6.0 (3.3 to 8.7)−2.7 (−5.6 to 0.2)−0.2 (−2.1 to 1.7)
3 mgPlacebo50 mg12–134.7 (1.0 to 8.4)2.1 (−0.4 to 4.5)1.1 (−1.2 to 3.5)4.4 (1.1 to 7.7)−4.0 (−7.5 to −0.6)−1.4 (−3.6 to 0.8)
3 mg50 mg50 mg11–128.5 (5.9 to 11.1)7.7 (3.6 to 11.9)6.1 (2.2 to 9.9)12.6 (6.3 to 18.8)−6.0 (−10.0 to −2.1)−0.1 (−2.1 to 1.8)
10 mg50 mg50 mg9–1010.6 (7.2 to 14.1)5.0 (0.49 to 9.4)6.1 (2.4 to 9.8)9.8 (3.4 to 16.2)−1.7 (−6.0 to 2.6)0.4 (−1.1 to 2.0)
25 mg50 mg50 mg14–1512.0 (7.1 to 16.9)10.7 (5.3 to 16.1)9.7 (5.4 to 14.1)16.3 (8.0 to 24.7)−2.1 (−4.1 to −0.1)3.1 (0.1 to 6.2)
50 mg50 mg50 mg1311.9 (7.2 to 16.5)8.5 (6.5 to 10.6)9.8 (5.7 to 13.9)10.9 (7.9 to 14.0)−0.3 (−2.6 to 2.0)1.1 (−0.4 to 2.7)

Biochemical markers of bone metabolism

Approximately 70% of participants were included in the per protocol analysis of the biochemical markers of bone metabolism. Table 4 shows the geometric mean percent changes from baseline in bone turnover markers over 5 years in women enrolled in the year 4 to 5 extension who received ODN 10, 25, or 50 mg weekly in the first 2 years of the trial. Treatment groups were combined according to the treatment received during years 4 to 5, either ODN 50 mg or placebo. For the resorption markers uNTX/Cr and sCTX, mean levels after 5 years of ODN treatment were substantially below baseline, whereas they had returned to near baseline following 3 years of placebo treatment after the initial 2 years of treatment with ODN. The bone resorption marker uDPD/Cr did not differ between groups, nor did it differ from baseline in either group (Table 4).

Table 4. Geometric Mean Percent Changes from Baseline (95% CI) in Biochemical Markers After 5 Years
 Years 1–2: 10, 25, or 50 mgYears 1–2: 10, 25, or 50 mg
 Year 3: placeboYear 3: 50 mg
 Years 4–5: placeboYears 4–5: 50 mg
Biochemical markern% change from baselinea (95% CI)n% change from baselinea (95% CI)
  • Values are % change from baseline (95% CI), geometric mean % change from baseline, back-transformed from the natural log. Biochemical markers were analyzed in the per protocol population and are presented in combined treatment groups: those receiving placebo for the last 3 years and those receiving clinically efficacious doses for all 5 years.

  • CI = confidence interval; uNTX/Cr = urinary N-telopeptides of type I collagen corrected for creatinine; sCTX = serum C-telopeptides of type 1 collagen; uDPD/Cr = urinary deoxypyridinolines corrected for creatinine; sBSAP = serum bone-specific alkaline phosphatase; sP1NP = serum N-terminal propeptide of type 1 collagen; sTRAP5b = serum tartrate-resistant acid phosphatase isoform 5b; s1CTP = serum cross-linked carboxy-terminal telopeptide of type 1 collagen.

  • a

    Geometric mean % change from baseline, back transformed from the natural log.

 uNTX/Cr253.6 (−18.2 to 31.3)26–55.6 (−69.8 to –34.7)
 sCTX25–11.1 (−30.4 to 13.4)27–53.0 (−63.5 to –39.4)
 uDPD/Cr2522.7 (−0.7 to 51.5)279.9 (−10.4 to 34.8)
 sBSAP25–10.1 (−15.5 to –4.4)29–15.0 (−22.5 to –6.9)
 sP1NP251.1 (−12.7 to 17.1)297.2 (−8.6 to 25.8)
 sTRAP5b1813.5 (3.7 to 24.1)2257.2 (41.0 to 75.2)
 s1CTP2723.2 (8.4 to 40.1)29246.5 (194.8 to 307.3)

The mean level of the bone formation marker sBSAP was slightly lower than baseline both after 5 years of ODN treatment and after switching to placebo following 2 years of ODN treatment. For the bone formation marker sP1NP, however, there was no difference from baseline in either group after 5 years (Table 4).

The levels of TRAP 5b, which is an indicator of the number of osteoclasts, and 1CTP, a substrate of the enzyme cathepsin K that is inhibited by ODN, were higher in the women receiving ODN 50 mg in years 3 to 5, compared to participants who received placebo in years 3 to 5 (Table 4).

Safety and tolerability

All women in the year 4 to 5 extension of this trial received ODN at some point during the trial, so there can be no direct comparison between ODN and placebo during this period in terms of safety. There were no meaningful distinctions between participants receiving placebo and those receiving ODN 50 mg during the last 2 years of the trial (Table 5). Skin AEs were evaluated specifically due to reports with another cathepsin K inhibitor, balicatib,18, 19 and there were no between-treatment group differences. There was a disparity in reported urinary tract infections (UTIs) between the ODN and placebo groups during the third year of the study.12 During years 4 and 5, a total of 16 women were reported with UTIs, at rates of 14% in the ODN group and 5% in the placebo group. Of 18 total UTIs, most of the cases were reported on the basis of dysuria. Four of the cases were documented by urine cultures; 16 cases were treated, 12 of them empirically based on symptoms; 2 cases were not treated and resolved spontaneously. Three of the women had a background history of UTIs, while 5 participants were reported with UTIs during the first 3 years of the study.

Table 5. Clinical AEs That Occurred During Years 4 and 5
 Treatment during years 4 and 5
Women with ≥1ODN 50 mg (n = 100) n (%)Placebo (n = 41) n (%)
  1. All participants received ODN during part or all of the trial (Fig. 1) and there is no true placebo for comparison.

  2. AE = adverse event; ODN = odanacatib.

AE89 (89)33 (81)
Serious AE18 (18)8 (20)
AE that led to discontinuation3 (3)0
Skin disorder21 (21)11 (27)
Urinary tract infection14 (14)2 (5)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

ODN is currently being investigated as a novel agent for the treatment of osteoporosis to improve bone mass and reduce risk of fractures. ODN has been previously shown to progressively increase BMD and decrease bone resorption markers during 3 years of treatment in this dose-ranging study of postmenopausal women. Resolution of the BMD and biochemical marker effects was seen after discontinuation of ODN treatment in year 3 of the study.12

In this planned year 4 to 5 study extension, lumbar spine BMD increased progressively throughout 5 years in those on continuous ODN treatment (combinations of ODN 10–50 mg). BMD at hip sites also increased progressively with ODN treatment, which appears to be different from the leveling off in BMD with bisphosphonates beyond approximately 3 years of treatment.9, 10, 20 Discontinuation of ODN treatment led to the return of BMD to baseline levels or slightly below, although a decline below baseline is expected in postmenopausal women receiving no treatment for several years.8, 21 This return to near baseline BMD shows reversibility of the ODN effect. Although the number of women in each individual treatment group was small, the consistent effects among the treatment groups confirm the pattern of BMD changes with continuous ODN treatment or discontinuation of treatment.

For the analysis of biochemical markers, we combined similar treatment groups, because the variability from the small number of participants in each individual treatment group obscures the overall treatment effect. In women on continuous ODN treatment (combinations of ODN 10–50 mg) throughout the 5 years of the trial, the bone resorption markers uNTX/Cr and sCTX remained reduced. On the other hand, bone formation markers sBSAP and sP1NP were transiently decreased, but over time, increased toward baseline levels.12 Compared with the women treated for 2 years with ODN and then treated for 3 years with placebo, the women who received continuous ODN had considerably lower levels of bone resorption markers, but similar levels of bone formation markers. The higher levels of the cathepsin K substrate 1CTP in participants on ODN treatment compared with placebo confirm inhibition of the enzyme, which leads to accumulation of the substrate. The higher levels of TRAP5b suggest that the number of osteoclasts22 was not diminished but had increased, consistent with findings from preclinical studies.13 Each of the biochemical markers returned toward baseline after discontinuation of ODN, showing the reversibility of the effect of ODN. Increases above baseline that were observed immediately upon ODN discontinuation were transient,12, 23 as has been seen with estrogen24 and denosumab,25 drugs that do not have long-term retention in bone.

Although the effect of ODN treatment on bone resorption markers is similar to that of the bisphosphonates and denosumab, its reduced effect on the bone formation markers distinguishes it from these conventional antiresorptive drugs.7, 9, 20, 26 A possible explanation for this differential effect on bone resorption and formation is that although ODN inhibits cathepsin K thereby interfering with osteoclast function, it does not reduce the number of active osteoclasts, as is observed with the bisphosphonates and denosumab. With maintenance of osteoclast number, the signaling between osteoclasts and osteoblasts may be maintained, and bone formation thus only minimally reduced. Other possible mechanisms may involve cell types other than osteoclasts and osteoblasts, such as osteocytes.27

The bone resorption marker DPD was not reduced by treatment with ODN. The reasons for this are not clear, but may involve alternative, cathepsin K-independent pathways that also degrade DPD. That other degradation pathways exist is supported by observations that DPD levels are also not decreased in patients with pycnodysostosis (a congenital disorder in which both alleles of the cathepsin K gene are mutated, with an absence of functioning cathepsin K and a high bone mass phenotype),28 and were not decreased in postmenopausal women with low BMD who were treated with another cathepsin K inhibitor in clinical development, ONO-5334.29 The degree of reduction of the biochemical markers of bone resorption, NTX and CTX, may overestimate the actual antiresorptive effect of ODN, because cathepsin K is involved in the release and subsequent processing of these telopeptides from the collagen matrix. Whereas inhibition of cathepsin K reduces bone resorption and reduces the release of these telopeptides, it may also alter processing of these peptides such that they are not detectable by the available immunoassays.

ODN exhibited a generally favorable safety and tolerability profile. No skin-related AEs similar to those observed with balicatib18, 19 were observed.

During the final 3 years of the current study, an imbalance was observed between the pooled placebo and the ODN 50-mg groups in the incidence of urinary tract infections, which was not observed in the first 2 years of the study. The onset of the UTIs did not seem to correlate with the duration of ODN treatment. Most of the cases were not documented by urine cultures and were treated empirically on the basis of symptoms.

Limitations of this year 4 to 5 extension of the odanacatib phase 2 trial are the small numbers patients remaining in each treatment group, which preclude formal statistical analysis, as prespecified in the study design. This trial extension was performed in order to obtain information about long-term treatment effects of odanacatib, even though the extension was expected to be underpowered for hypothesis testing.

In conclusion, in this phase 2 trial of postmenopausal women, 5 years of ODN treatment increased BMD at the spine and hip. A more limited effect of ODN on markers of bone formation, and rapid resolution of treatment effect may differentiate it from antiresorptive agents such as the bisphosphonates. ODN was generally well-tolerated in this study.

The efficacy of ODN in preventing fractures of the hip, nonvertebral sites, and fractures of the spine is being investigated in an ongoing phase 3 fracture trial of over 16,000 postmenopausal women with osteoporosis. The results of that trial will determine whether ODN is effective in reducing fractures.

Disclosures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

AD, ALombardi, CLBDT, CDS, ER, and ALeung are employees of Merck Sharp & Dohme Corp (MSD). BL has received grant support, consultancy fees and has board membership with MSD. NB has received grant support and consultancy fees from MSD. HB has received consultancy fees and travel support from MSD. JRP has received grant support from MSD. NG and HR report no conflicts.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

We thank Jennifer Pawlowski, MS, for her assistance in submitting the paper. This study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc.

Authors' roles: Study design: HB, ALe, ALo, CD. Study conduct: CD, ALo, AD. Data analysis: CLBDT. Data interpretation: BL, NB, HB, NG, HR, JRP, AD, ALo, CLBDT, ER, Ale. Drafting manuscript: BL, ER, ALe. Revising manuscript content: BL, NB, HB, NG, HR, JRP, AD, ALo, CLBDT, CD, ER, ALe. Approving final version of manuscript: BL, NB, HB, NG, HR, JRP, AD, ALo, CLBDT, CD, ER, Ale. CLBDT and ALe take responsibility for the integrity of the data analysis.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  • 1
    Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377(9773):127687.
  • 2
    Compston J. Osteoporosis: social and economic impact. Radiol Clin North Am. 2010;48(3):47782.
  • 3
    Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007;22(3):46575.
  • 4
    Reszka AA, Rodan GA. Mechanism of action of bisphosphonates. Curr Osteoporos Rep. 2003;1(2):4552.
  • 5
    Russell RG. Bisphosphonates: from bench to bedside. Ann N Y Acad Sci. 2006;1068:367401.
  • 6
    Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011;48(4):67792.
  • 7
    Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):75665.
  • 8
    Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996;348(9041):153541.
  • 9
    Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH III, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999;282(14):134452.
  • 10
    Miller PD, Recker RR, Reginster JY, Riis BJ, Czerwinski E, Masanauskaite D, Kenwright A, Lorenc R, Stakkestad JA, Lakatos P. Efficacy of monthly oral ibandronate is sustained over 5 years: the MOBILE long-term extension study. Osteoporos Int. 2012 Jun; 23(6):174756.
  • 11
    Bone HG, McClung MR, Roux C, Recker RR, Eisman JA, Verbruggen N, Hustad CM, DaSilva C, Santora AC, Ince BA. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J Bone Miner Res. 2010;25(5):93747.
  • 12
    Eisman JA, Bone HG, Hosking DJ, McClung MR, Reid IR, Rizzoli R, Resch H, Verbruggen N, Hustad CM, DaSilva C, Petrovic R, Santora AC, Ince BA, Lombardi A. Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J Bone Miner Res. 2011;26(2):24251.
  • 13
    Masarachia PJ, Pennypacker B, Pickarski M, Scott KR, Wesolowski GA, Smith SY, Samadfam R, Goetzmann JESBB, Kimmel DB, Duong LT. Odanacatib reduces bone turnover and increases bone mass in lumbar spine of skeletally mature ovariectomized rhesus monkeys. J Bone Miner Res. 2011;27(3):50923.
  • 14
    Cusick T, Chen CM, Pennypacker BL, Pickarski M, Kimmel D, Scott BB, Duong LT. Odanacatib treatment increases hi bone mass and cortical thickness by preserving endocortical bone formation and stimulating periosteal bone formation in ovariectomized adult rhesus monkey. J Bone Miner Res. 2011;27(3):52437.
  • 15
    Khosla S. Odanacatib: location and timing are everything. J Bone Miner Res. 2012;27(3):5068.
  • 16
    Jerome C, Missbach M, Gamse R. Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys. Osteoporos Int. 2012 Jan; 23(1):33949.
  • 17
    Stoch SA, Wagner JA. Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther. 2008;83(1):1726.
  • 18
    Peroni A, Zini A, Braga V, Colato C, Adami S, Girolomoni G. Drug-induced morphea: report of a case induced by balicatib and review of the literature. J Am Acad Dermatol. 2008;59(1):1259.
  • 19
    Runger TM, Adami S, Benhamou CL, Czerwinski E, Farrerons J, Kendler DL, Mindeholm L, Realdi G, Roux C, Smith V. Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib. J Am Acad Dermatol. 2012 Mar;66(3):e 8996. DOI: 10.1016/j.jaad.2010.11.033.
  • 20
    Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296(24):292738.
  • 21
    Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med. 1995;333(22):143743.
  • 22
    Henriksen K, Tanko LB, Qvist P, Delmas PD, Christiansen C, Karsdal MA. Assessment of osteoclast number and function: application in the development of new and improved treatment modalities for bone diseases. Osteoporos Int. 2007;18(5):6815.
  • 23
    Binkley N, Bone H, Eisman J, Hosking D, Langdahl B, Reid I, Resch H, Rodriguez Portales J, Petrovic R, Hustad C, DaSilva C, Santora A, Lombardi A. Effect of odanacatib on bone density and bone turnover markers in postmenopausal women with low bone mineral density: year 4 results [Internet]. J Bone Miner Res. 2010;25(Suppl 1):[cited 2012 July 2]. Available from: http://www.asbmr.org/Meetings/AnnualMeeting/AbstractDetail.aspx?aid=a431b2ef-f2b9-4c0d-8f7b-8d0fa50da6f4.
  • 24
    Gallagher JC, Rapuri PB, Haynatzki G, Detter JR. Effect of discontinuation of estrogen, calcitriol, and the combination of both on bone density and bone markers. J Clin Endocrinol Metab. 2002;87(11):491423.
  • 25
    Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008;43(2):2229.
  • 26
    Stakkestad JA, Lakatos P, Lorenc R, Sedarati F, Neate C, Reginster JY. Monthly oral ibandronate is effective and well tolerated after 3 years: the MOBILE long-term extension. Clin Rheumatol. 2008;27(8):95560.
  • 27
    Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26(2):22938.
  • 28
    Nishi Y, Atley L, Eyre DE, Edelson JG, Superti-Furga A, Yasuda T, Desnick RJ, Gelb BD. Determination of bone markers in pycnodysostosis: effects of cathepsin K deficiency on bone matrix degradation. J Bone Miner Res. 1999;14(11):19028.
  • 29
    Eastell R, Nagase S, Ohyama M, Small M, Sawyer J, Boonen S, Spector T, Kuwayama T, Deacon S. Safety and efficacy of the cathepsin K inhibitor, ONO-5334, in postmenopausal osteoporosis—the OCEAN study. J Bone Miner Res. 2011;26(6):130312.