Introduction

Postmenopausal osteoporosis is characterized by a loss of bone mass, which results from bone resorption exceeding bone formation leading to microstructural bone defects and increased fracture risk [1]. As populations age, osteoporotic fractures are an increasing problem and represent a substantial economic and social burden [2–4].

Currently available therapeutic agents for treating patients with postmenopausal osteoporosis and preventing fractures include anti-resorptive agents, such as bisphosphonates and the human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL), denosumab, and the anabolic agent teriparatide, which has been shown to prevent vertebral fractures [5]. The US Food and Drug Administration (FDA), however, has recommended restricting the use of bisphosphonates to 3–5-year duration, except in patients still at increased risk of fracture [6]. The FDA has recommended that teriparatide not be used for more than 2 years over a patient’s lifetime [7]. There is, therefore, a need for long-term treatment for osteoporosis with a new mechanism of action to provide greater choices to physicians and patients.

Odanacatib (ODN) has a novel mode of action, selectively inhibiting cathepsin K (CatK), a lysosomal cysteine protease highly expressed in osteoclasts, which degrades the collagen matrix components of bone [8]. Unlike anti-resorptive agents that reduce the number of osteoclasts to decrease bone resorption and secondarily reduce osteoblast number, ODN specifically inhibits osteoclast bone resorption activity, while maintaining osteoclast number and viability [9–11].

ODN was studied in a placebo-controlled, double-blind, randomized, 2-year phase 2b dose-ranging study in postmenopausal women with low bone mineral density (BMD) [12]. Patients completing the first 2 years of this study could be eligible for extension studies, first for 1 year and then for a further 2-year period, providing up to 5-year exposure to ODN [13, 14]. These studies showed that treatment with ODN progressively increased BMD and decreased bone resorption markers, whereas bone formation markers remained near baseline. Treatment with ODN for up to 5 years was generally well tolerated. A further 5-year extension (years 6 to 10) was planned to evaluate the long-term efficacy and safety of weekly oral ODN 50 mg. Here, we present results from the prespecified interim year 8 analysis of this 5-year extension.

Methods

Study design

This was a prespecified interim analysis of an ongoing 5-year extension (years 6 to 10) to a phase 2b clinical study investigating the efficacy and safety of ODN for the treatment of osteoporosis in postmenopausal women (ClinicalTrials.gov NCT00112437; protocol number 004) (Fig. 1). Study design and results for the initial 2-year study [12] and subsequent 1-year [13] and 2-year extension [14] phases have been reported in detail previously.

Fig. 1
figure 1

Schematic of study design. Group A received ODN 50 mg for 8 years or ODN 25 mg for 2 years followed by 6 years of ODN 50 mg; group B received ODN 50 mg for the last 6 years and placebo or ODN 3 or 10 mg during the first 2 years; group C received ODN 50 mg for the last 5 years and placebo or ODN 3 mg during the first 2 years and placebo in year 3; and group D received ODN 50 mg for the last 3 years, placebo during the previous 3 years, and doses of ODN between 10 and 50 mg during the first 2 years. aPatient groups included in the year 8 interim analysis had been receiving ODN 25 or 50 mg once weekly for between three and eight consecutive years at the time of this analysis, bBMD was measured using dual-energy X-ray absorptiometry, c n = 24 for lumbar spine and n = 22 for other sites, and d n = 22 for lumbar spine and n = 21 for other sites. BMD bone mineral density, ODN odanacatib in milligram; dosing was once weekly

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In the initial 2-year, randomized, double-blind, multicenter, dose-finding study, eligible postmenopausal women with low BMD were assigned, using a computer-generated randomized allocation schedule, to receive placebo or oral ODN, taken without regard to food intake, at 3, 10, 25, or 50 mg once weekly (Fig. 1). For year 3, all women in each of the five original dose groups were re-randomized to receive ODN 50 mg once weekly or placebo in a 1:1 ratio. For years 4 and 5, all women who had received ODN 3 mg once weekly or placebo in years 1 and 2 were switched to ODN 50 mg once weekly; other patients remained on the same regimen as in year 3. For the present extension, all women received open-label ODN 50 mg once weekly, attended clinic visits every 6 months, and were followed up by telephone every 3 months.

Ten discrete patient subgroups were defined based upon the treatments received since the initial randomization into the study (Fig. 1). An interim analysis was conducted at year 8, with a focus on the long-term BMD effects of ODN. For this reason, and in order to describe the results with greater clarity, patient subgroups were combined in four different treatment groups based on their exposure to effective ODN doses. The treatment groups are described below and presented in greater detail in Fig. 1.

  • Group A (n = 28) included patients treated with ODN 50 mg continuously for 8 years or with ODN 25 mg during the first 2 years followed by 6 years of ODN 50 mg.

  • Group B (n = 34) included patients who were treated with ODN 50 mg for the last 6 years and who had received placebo or lower doses of ODN (3 or 10 mg) during the first 2 years.

  • Group C (n = 23) included patients treated with ODN 50 mg for the last 5 years and who had received placebo or ODN 3 mg during the first 2 years and placebo in year 3.

  • Group D (n = 32) included patients treated with ODN 50 mg for the last 3 years and who had received placebo during the previous 3 years and doses of ODN between 10 and 50 mg during the first 2 years.

All participants were also provided with supplemental vitamin D3 (5600 IU once weekly), and those with a calcium intake <1000 mg/day (assessed via a dietary calcium questionnaire) were given a daily supplement of calcium carbonate (500 mg/day). The study was conducted in accordance with Good Clinical Practice guidelines and was approved by local institutional review boards.

Participants

The initial 2-year phase 2b study enrolled postmenopausal women, aged 45–85 years, with no previous history of fragility fractures and a BMD T-score ≤ −2.0 at the lumbar spine, trochanter, femoral neck, or total hip but not <−3.5 at any site. Women completing year 5 of the extension study were eligible for enrollment in this additional 5-year extension study, unless they demonstrated significant clinical or laboratory abnormalities that were judged to cause additional risks or to complicate interpretation of the study results. BMD at the year 5 visit was not an inclusion/exclusion criterion for this extension study. Patients gave written informed consent prior to enrollment at the initiation of the study and at the beginning of each subsequent extension phase.

End points

Details of study procedures have been described previously [12–14]. Briefly, BMD was measured by dual-energy X-ray absorptiometry scans (using lunar and hologic instruments at the various sites) at the hip (total, femoral neck, and trochanter), lumbar spine, and 1/3 radius at months 72, 84, and 96. All BMD scans were centrally evaluated. Biochemical markers of bone turnover (serum bone-specific alkaline phosphatase [sBSAP], serum N-terminal propeptide of type I collagen [sP1NP], urinary N-telopeptide of type I collagen corrected for creatinine [uNTx/Cr], serum C-telopeptide of type I collagen [sCTx], serum cross-linked carboxy-terminal telopeptide of type I collagen [s1CTP], and serum tartrate-resistant acid phosphatase isoform 5b [sTRAP 5b]) were measured in the fasting state (at months 72, 84, and 96 for sP1NP and uNTx and at month 96 for the other biomarkers). Individual biomarker assays (Synarc, Lyon, France) were as described previously [14].

The primary efficacy end point of this 5-year extension is percent change from baseline in BMD at the lumbar spine at years 8 and 10. Secondary efficacy end points include percent change from baseline in BMD for trochanter, femoral neck, total hip, and 1/3 radius and change from baseline in biochemical markers of bone resorption (uNTx/Cr and sCTx), sTRAP 5b (a biomarker of osteoclast numbers), s1CTP (a C-terminal fragment of collagen produced by matrix metalloproteinases which is further digested by CatK to generate CTx and is, therefore, a target engagement marker for CatK inhibition) [15], and biochemical markers of bone formation (sBSAP and sP1NP), analyzed as a log-transformed fraction from baseline. Baseline was defined as the first study visit in the initial phase 2b study for all end points.

Safety was evaluated based on the incidence of adverse events (AEs), which were recorded throughout, and clinical and laboratory evaluations performed at each 6-monthly visit. All patients who received at least one dose of study medication during the years 6 to 8 extension period were included in the safety analysis. Special attention was given to skin, respiratory, dental, and delayed fracture union events.

Statistical analysis

All results were summarized as descriptive analyses using summary statistics. BMD end points were evaluated for the full analysis set (FAS) as percent change from baseline in raw arithmetic means with 95 % confidence intervals (CIs). Biochemical markers were evaluated for the per protocol (PP) population as log-transformed fraction from baseline and transformed back to a geometric mean percent change from baseline with 95 % CIs. Missing data were not imputed or estimated. Safety and tolerability were evaluated in the all-patients-as-treated (APaT) population. One interim analysis was to be performed at year 8.

Results

Patients

A total of 117 women entered the years 6 to 10 extension of the initial study. At the time of this year 8 analysis, 28 patients had received ODN 25 or 50 mg once weekly for eight consecutive years (group A), while 34 patients had taken ODN 50 mg for six consecutive years (group B), 23 patients for five consecutive years (group C), and 32 patients for three consecutive years (group D). At year 8, the FAS population evaluable for lumbar spine BMD comprised 87 patients, and 57 women were included in the PP population evaluable for biomarkers (Fig. 1). Baseline demographics and characteristics at study entry of the women entering the years 6 to 10 extension are shown in Table 1.

Table 1 Baseline demographics and characteristics
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Bone mineral density

Lumbar spine BMD at year 8 increased from baseline after treatment with ODN 50 mg for all groups (Fig. 2). Mean increases in lumbar spine BMD (95 % CI) were 14.8 % (11.0, 18.6) for patients in group A, 12.8 % (10.0, 15.7) for group B, 12.9 % (8.1, 17.7) for group C, and 4.6 % (2.4, 6.7) for group D. Similar patterns of results were observed for BMD for trochanter, femoral neck, and total hip compared with baseline (Fig. 2). Results for BMD at 1/3 radius showed a slight decrease compared with baseline. Time-effect profiles for patients who received ODN 25 or 50 mg once weekly for eight consecutive years are shown in Fig. 3 for the FAS population and for the “completer” population with complete data at months 60 to 96.

Fig. 2
figure 2

Percent change from baseline in BMD at year 8 (FAS population, ODN 25a or 50 mg once weekly). Group A received ODN 50 mg for 8 years or ODN 25 mg for 2 years followed by 6 years of ODN 50 mg, group B received ODN 50 mg for the last 6 years and placebo or ODN 3 or 10 mg during the first 2 years, group C received ODN 50 mg for the last 5 years and placebo or ODN 3 mg during the first 2 years and placebo in year 3, and group D received ODN 50 mg for the last 3 years, placebo during the previous 3 years, and doses of ODN between 10 and 50 mg during the first 2 years. aFourteen patients in group A received ODN 25 mg for 2 years before receiving ODN 50 mg (see Fig. 1), b n = 24 for lumbar spine and n = 22 for other sites, and c n = 22 for lumbar spine and n = 21 for other sites. BMD bone mineral density, FAS full analysis set, ODN odanacatib, SE standard error

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Fig. 3
figure 3

Percent change from baseline in BMD over time for patients receiving up to 8 years of continuous treatment with ODN 25a or 50 mg once weekly (group A) for a FAS population and b “completer” population (each time point corresponds to the same patients followed over time). aFourteen patients in group A received ODN 25 mg for 2 years before receiving ODN 50 mg (see Fig. 1). BMD bone mineral density, FAS full analysis set, ODN odanacatib, SE standard error

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Bone turnover biomarkers

Approximately 50 % of participants were included in the PP analysis of the biochemical markers of bone turnover. Table 2 shows the geometric mean percent changes from baseline in these markers at year 8. At year 8, biomarkers of bone resorption were substantially inhibited, with uNTx/Cr and sCTx values reduced compared with baseline. There was no appreciable variation in uNTx/Cr or sCTx values between the groups who had received continuous ODN treatment for between 3 and 8 years. Levels of sTRAP 5b and s1CTP increased in all groups compared with baseline. There was no significant change in the bone formation markers sBSAP and sP1NP.

Table 2 Geometric mean percent changes from baseline (95 % CI) in biochemical markers of bone turnover at year 8 (PP population)
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Safety and tolerability

All 117 patients who entered and received treatment in this 5-year extension were included in the extension safety analysis (APaT population). A summary of AEs is reported in Table 3. Overall, 114 (97.4 %) patients reported at least one AE, and 12 (10.3 %) patients had AEs that were thought by the local investigator to be related to treatment with ODN. There was no clinically important difference among the four treatment groups in the proportions of patients with a drug-related AE or who discontinued study participation because of an AE. Of the 31 (26.5 %) patients who recorded a serious AE, two experienced events that were thought by the local investigator to be related to treatment with ODN; one patient in group A discontinued her participation because of a basal cell carcinoma thought by the investigator to be drug related and a second patient in group A reported nausea which was also assessed by the investigator to be drug related but continued treatment. Two additional patients discontinued participation in the study because of serious AEs; one patient in group D was diagnosed with gastric cancer that was considered unrelated to study medication, and one patient in group B developed pancreatic cancer that was considered unrelated to study medication. This latter patient died during the study period (secondary to metastatic pancreatic carcinoma), 2 months after discontinuing the study.

Table 3 Summary of AEs reported during the years 6 to 8 extension period (APaT population)
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Because of reports of adverse skin effects with another CatK inhibitor, balicatib [16, 17], skin-related AEs were evaluated with particular interest. In total, 39 (33.3 %) patients reported at least one dermatologic AE and 4 (3.4 %) patients experienced AEs that were considered by the local investigator to be related to ODN (Table 3); one patient in group A was reported to have basal cell carcinoma, one patient in group B was reported to have hyperkeratosis, and two patients in group C were reported to have rash (not otherwise characterized) and alopecia areata, respectively. No cases of morphea-like skin lesions were reported.

Also of particular interest, because of reports of adverse experiences with approved osteoporosis treatments or other CatK inhibitors, were any cases of osteonecrosis of the jaw (ONJ), serious respiratory AEs, or delayed fracture union events. Ultimately, there were no reports of ONJ and no episodes of delayed fracture union. The only serious respiratory AEs were a case of infectious exacerbation of chronic obstructive pulmonary disease and a pneumothorax resulting from a broken rib sustained in a fall. In addition, a diaphyseal fracture of the femur was reported as a serious AE in a patient with a history of fracture of the same femur 20 years prior.

Discussion

The results presented here demonstrate that extended treatment with ODN 25 or 50 mg once weekly for up to 8 years resulted in continuation or maintenance of increases in BMD at multiple sites compared with baseline. In those women who had received continuous ODN treatment for 8 years (group A “completer population”, wherein patients received ODN 25 or 50 mg for 2 years before receiving ODN 50 mg for 6 years), lumbar spine and trochanter BMD continued to increase progressively up to year 6, after which the rate of increase slowed or the increases were maintained up to year 8. At the femoral neck and total hip, BMD gains during the first 5 years of continuous ODN treatment were maintained for the following 3 years of continuous ODN treatment. Between years 6 and 8, 1/3 radius BMD remained stable at a level within 5 % below baseline. As there was no placebo group beyond 5 years, the changes in BMD at a particular site relative to untreated women cannot be determined. Results from the earlier phases of the study indicate a protective effect of ODN on 1/3 radius BMD; during the initial 2 years of the study, 1/3 radius BMD steadily decreased in the placebo group, whereas it was maintained in the ODN 25- and 50-mg groups [12]. Similarly, after 5-year continuous ODN treatment, 1/3 radius BMD 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 [14]. In comparison, using a high-resolution peripheral quantitative computed tomography technique, which measures volumetric BMD (vBMD) rather than areal BMD as in our study, and a different region of interest, a study in postmenopausal women who were not receiving bone-active drugs has shown site-specific changes at the distal radius, with a change in total density of −1.7 % within 1 year [18]. With this technique, alendronate has been shown to prevent decline of, and denosumab to increase, distal radius BMD in postmenopausal women over 1 year [19]. Another study, measuring areal BMD, found that alendronate reduced the decline of, and denosumab increased, distal radius BMD in postmenopausal women over 1 year [20]. In the case of ODN, vBMD assessment within a randomized, placebo-controlled, 2-year trial has shown a significant treatment difference from placebo (3.84 %) at the distal radius [21]. Significant differences from placebo were also found in trabecular vBMD, cortical vBMD, cortical thickness, cortical area, and strength (failure load), estimated using finite element analysis of HR-pQCT scans (treatment difference at radius, 2.64 %). At the distal radius, ODN significantly increased trabecular thickness and bone volume/total volume versus placebo. At a more proximal radial site, ODN attenuated the increase in cortical porosity found with placebo (treatment difference −7.7 %, p = 0.066). In the current study, improvements in BMD were generally greatest in those patients who had received continuous ODN 50 mg for the longest period of time. It is unknown whether the increases or maintenance of BMD with ODN are a consequence of increased mineralization, as observed in animal models of fracture healing [22], or secondary to modeling effects, with reduced remodeling coupled with increased modeling-based bone formation, as observed in ODN-treated animals [23]. One study in ODN-treated animals reported an increase in the bone formation rate at the periosteal level, thus likely a modeling process, while mineralization apposition rate was not modified at sites with decreased remodeling [9]. Conservation of modeling-based formation has also been seen in denosumab-treated animals [24].

The analysis of biochemical markers indicates that bone resorption is reduced by ODN and that this effect is sustained with long-term ODN treatment. The reductions from baseline in the bone resorption markers uNTx/Cr and sCTx were similar for each treatment group receiving continuous ODN for between 3 and 8 years. The bone formation markers sBSAP and sP1NP remained near baseline levels for all of the treatment groups. Previously published data from this study showed an initial decrease in sBSAP and sP1NP for the first 6 months of ODN treatment, with gradual increases thereafter back to baseline levels by the end of year 2 [12]. Another 2-year, double-blind, randomized study of ODN 50 mg or placebo once weekly in postmenopausal women with low BMD also found that sP1NP initially decreased during the first 6 months but did not differ from placebo by 2 years [25]. Together, these results indicate that bone formation is only moderately and transiently affected by ODN therapy. Levels of sTRAP 5b, an indicator of osteoclast cell number [26], were higher than baseline across the treatment groups. This is consistent with findings from preclinical studies suggesting that osteoclast numbers are unaffected or tend to increase with ODN [10, 27]. Since s1CTP is a substrate for CatK [15], it would be expected to accumulate in the setting of a CatK inhibitor. Indeed, levels of s1CTP were elevated, with the highest levels in the treatment groups exposed to continuous ODN for the longest period of time. Unlike the currently available anti-resorptive agents, bisphosphonates and denosumab, which substantially reduce both markers of bone resorption and bone formation, ODN appears to reduce the levels of bone formation markers only transiently and modestly. A possible explanation for this differential effect on bone resorption and formation is that although ODN inhibits CatK, thereby preventing the breakdown of bone collagen by osteoclasts, it does not reduce the number of osteoclasts, as do bisphosphonates and denosumab [28]. With ODN treatment, osteoclasts are still present; therefore, the signaling between the bone-resorbing osteoclasts and bone-forming osteoblasts in bone-remodeling units may be maintained, allowing the preservation of bone formation [29, 30]. Although bone remodeling at the tissue level is reduced by ODN, continued modeling could account for the maintenance of bone formation markers.

Overall, ODN appears to be well tolerated with prolonged use. Special attention was given to skin, respiratory, dental, and delayed fracture union events because of reports of related pathology with approved osteoporosis therapies or other CatK inhibitors previously in development [16, 17, 31, 32]. After up to 8 years of treatment with ODN, no cases of morphea-like skin reactions, ONJ, or delayed fracture union were reported in this study.

A limitation of this years 6 to 10 extension of the ODN phase 2b study is the low patient number remaining in each group and potential bias from patients who discontinued from the study over time. The lack of randomization (patients were carried over from their originally assigned treatment) and the open-label nature of this extension may cause additional bias. Although there was no placebo group, the study can be used to detect AEs that may emerge after long-term treatment. This study extension was performed in order to obtain information about long-term treatment effects of ODN, even though it was understood that the extension would be underpowered for hypothesis testing.

In conclusion, ODN 50 mg once weekly effectively increased BMD in women with osteoporosis and was well tolerated during long-term use. Furthermore, efficacy was maintained up to 8 years of treatment. Preliminary results of the phase 3 fracture outcome trial (Long-Term Odanacatib Fracture Trial [LOFT]), involving over 16,000 postmenopausal women with osteoporosis, have shown that ODN significantly reduces the risk of new morphometric vertebral, clinical hip, and clinical non-vertebral fractures compared with placebo [33].