Eldecalcitol combined with raloxifene or bisphosphonates administered for 6 months to postmenopausal women with osteoporosis who were drug-naïve or who had switched medications significantly reduced and maintained TRACP-5b values within the reference range.

Eldecalcitol (ELD) is a novel active vitamin D3 analogue with a hydroxypropyloxy group at 2β-position of 1α, 25-dihydroxyvitamin D3. It significantly increases bone mineral density (BMD) at the lumbar spine and total hip, and decreases bone resorption markers and incidence of both vertebral and non-vertebral (wrist) fractures compared with alfacalcidol (ALF). A previous study demonstrated that inhibitory effect of ELD on bone resorption which mechanisms differ from those of other antiresorptive drugs such as raloxifene (RLX) and bisphosphonates (BP). Based on these findings, ELD has been approved for treating osteoporosis in Japan. First-line treatment for osteoporosis typically comprises RLX and BP; however, serum vitamin D status affects the increase in BMD at the lumbar spine in osteoporotic women. Patients in most randomized clinical trials of the effects of antiresorptive drugs were treated with supplemental calcium and vitamin D, because vitamin D deficiency seems a common health issue among elderly individuals, especially among those with osteoporosis.

Rationale behind research:

The suppressive use of antiresorptive drugs plus ELD on bone resorption require clinical evaluation. Therefore, present study was conducted, so as to address this greater area of unmet need.

Objective:

To retrospectively analyze whether concomitant raloxifene (RLX) or bisphosphonates (BP) plus eldecalcitol (ELD) has excessive suppressive effects on a bone resorption marker during the first 6 months of treatment in postmenopausal women in real world setting

Note: Japanese criteria for primary osteoporosis- Low BMD (T score < - 2.5) or presence of osteoporotic fractures. All patients had no secondary causes of osteoporosis, no history of treatment with glucocorticoids or drugs affecting bone metabolism, no fractures for 6 months before starting treatment and no new fractures arising during treatment. Serum Ca, P, and ALP in all patients represented within normal range.

Study outcomes

Bone Metabolic Marker: Levels of bone resorption marker, serum tartrate resistant acid phosphatase-5b (TRACP-5b), at the start of RLX or BP plus ELD treatment and within 6 months thereafter were measured.

Time points: Efficacy: Baseline and 6 months

Baseline: No significant differences were observed between groups in age or baseline TRACP-5b values.

Outcomes

• Drug naive group: Mean and median percent changes of TRACP-5b in both RLX+ELD and BP+ELD groups significantly decreased during the first 6 months by 34.8 and 54.1%, respectively, and 39.7% and 61.0% (p = 0.002), respectively, which is consistent with BP being a more potent antiresorptive drug than RLX. The rates of patients with TRACP-5b decreasing beyond MSC did not significantly differ between RLX+ELD and BP+ELD groups (77.8% vs 94.2%, p=0.067). Values of TRACP-5b decreased below reference value (< 120 mU/dL) in 9 (17.3%) of 52 patients in BP+ELD group, but not in RLX+ELD group (p = 0.057). Among these nine patients, four, four, and one had TRACP- 5b values of 100-120, 80-100, and 79 mU/dL, respectively.
• VD-switch group: Mean and median percent changes of TRACP-5b in both treatment groups significantly decreased during first 6 months. The mean and median percent changes in RLX+ELD and BP+ELD were -21.1 and -13.0%, respectively, and -24.5 and -21.9%, respectively, with no significant differences (p = 0.532). The rates of patients with TRACP-5b values that decreased below MSC in RLX+ELD and BP+ELD groups were 70.5% vs 60.5% (p = 0.137). Five (3.6%) of 139 and three (3.9%) of 76 patients in RLX+ELD and BP+ELD groups, respectively, had TRACP-5b values that decreased below reference range (p = 0.897). Stratification of the baseline values significantly differed among the highest, middle, and lowest tertiles of patients in the RLX+ELD group (-30.3, -21.1 and -11.6%, respectively; p < 0.001 for trend). The highest and lowest tertiles significantly differed (p < 0.001). The tendency was same in ELD+BP group (-30.4, -15.7 and 7.7%, respectively; p <0.001 for trend), and the highest and lowest tertiles also significantly differed (p < 0.001).
  

ELD is more effective than ALF in preventing osteoporotic fractures with a significant suppression of bone resorption markers in patients with osteoporosis. In this study, it was shown that concomitant RLX or BP with ELD significantly decreased levels of the bone resorption marker TRACP-5b in the drug-naïve group. ELD decreases bone resorption markers via a different mechanism from RLX and BP (4), but RLX or BP combined with ELD during the first 6 months of treatment did not severely suppress bone resorption markers in the drug-naïve group.

To our knowledge, this is the first clinical comparison of postmenopausal women with osteoporosis who were switched from RLX or BP plus ALF to RLX or BP with ELD. The reasons why replacing ALF with ELD further and significantly inhibited TRACP-5b were not clearly understood. However, a previous study demonstrated that the inhibitory effect of ELD on bone resorption in vivo is elicited via the suppression of receptor activator of NF-κB ligand (RANKL) expression in osteoblasts. Another study showed that ELD reduces the number and activities of osteoclasts by decreasing the number of preosteoblastic cells that interact with osteoclast precursors. Levels of TRACP-5b were obviously decreased far more in the highest, compared with the lowest tertile, indicating that ELD can further, but not excessively, suppress bone resorption markers, even in patients who had previously taken ALF combined with RLX or BP.