Risedronate 5 mg IR daily significantly reduces the incidence of major fragility fractures in women with postmenopausal osteoporosis and of vertebral fractures in subjects receiving glucocorticoids [11
]. Fracture risk reduction occurs within months of beginning therapy and appears to persist with treatment for at least 7 years [15
]. Weekly and monthly IR dosing forms of risedronate were developed to make dosing more convenient and acceptable and in the hope of improving persistence with treatment [18
]. However, all of these regimens, like other oral bisphosphonate dosing schedules, require dosing at least 30 min before food or drink. Even taking oral bisphosphonates with tap water or bottled water can decrease bioavailability [20
]. None of the current oral bisphosphonate dosing schemes solves the possible detrimental effect of poor compliance with dosing instructions on bisphosphonate absorption and clinical effectiveness. That the impact of poor compliance can be important was demonstrated by the significant blunting of the BMD response to risedronate IR given between meals compared to being taken before breakfast [21
]. The unique risedronate weekly DR formulation, consisting of both the addition of a chelating agent and the enteric coating, promotes disintegration of the tablet in the small intestine. This formulation obviates the food effect and minimizes the concern about poor compliance.
Extending the observations from the 12-month analysis of this study, the results presented here demonstrate that the increases in bone mineral density and the decreases in biochemical markers of bone turnover at 2 years were at least as great with both DR dosing regimens compared to the risedronate IR daily dose. The greater responses in lumbar spine and femoral trochanter BMD and serum CTX to the DR doses are unexpected. It is unlikely that this is explained simply by a difference in the 5-mg daily dose and the 35-mg weekly dose since the BMD and marker responses to risedronate 5 mg daily IR and 35 mg weekly IR were not different over a 2-year treatment interval [18
]. The greater response could be due to increased bioavailability of the DR formulation compared to the IR daily dose. Enteric coating did not affect bioavailability of alendronate 70 mg [22
]. Since a formal dose-ranging study with risedronate was never performed, it is uncertain that the 5 mg daily IR or 35 mg weekly IR dose is at the top of the dose–response curve. Supporting this possibility is the observation that the changes in lumbar spine and proximal femur BMD and in BTMs were somewhat greater with a weekly IR dose of risedronate at 50 mg compared to those observed with the 5 mg daily or 35 mg weekly doses [18
]. Thus, it is possible that a modest increased bioavailability could result in greater responses in bone turnover and bone mineral density. However, the increased response observed with risedronate 50 mg weekly IR dose was observed within the first 6 months of treatment and did not separate further from the lower doses with continued therapy out to 2 years. Furthermore, in the limited testing of risedronate DR bioavailability, no clear difference was noted compared to IR dosing [23
Another possible explanation is that compliance with the IR daily dosing instructions was suboptimal, even in the setting of a clinical trial where subjects were seen and reminded of proper dosing instructions more often than occurs in clinical practice. The protection from the food effect afforded by the DR formulation would, in theory, obviate the effect of poor compliance. Subjects were seen less frequently during the second year of our study than during the first year, and it is possible that compliance with dosing diminished with continued use. This effect would not be captured by the standard strategy of assessing treatment compliance by simply counting tablets taken by the study participants. If suboptimal compliance is the explanation for the observed difference in our clinical study, it is probable that an even greater difference would occur between the DR and IR preparations in daily practice.
The histomorphometric results seen in this study were consistent with those seen after 1, 3, and 5 years in previous 5 mg risedronate IR studies in women with postmenopausal osteoporosis [24
]. In those studies, no histological abnormalities or defects in matrix mineralization were noted, and long-term treatment with risedronate preserved bone material properties. Bone turnover was reduced by 1 year to levels observed in healthy premenopausal women, and turnover was not reduced further with longer term treatment. In our study, after 2 years of treatment, no histological or mineralization abnormalities were observed in any of the risedronate-treated groups. Importantly, persistent bone turnover was evident as noted by the presence of tetracycline label in all 45 biopsy samples. This contrasts with the histomorphometric results with alendronate and denosumab that demonstrated absent tetracycline labels in many subjects [29
]. This apparent difference in the level of turnover observed on treatment is consistent with the study by Rosen and colleagues in which the approved dose of alendronate (70 mg weekly) reduced markers of bone turnover significantly more than did the approved dose of risedronate IR (35 mg weekly) [31
]. The clinical implications of the reported differences among different drugs on indices of bone turnover are not known, but knowing that bone remodeling is not “over suppressed” with risedronate is reassuring.
Overall, the tolerability of the weekly DR regimens was similar to that observed with the daily IR treatment. These data are consistent with previous studies in which the tolerability was similar in subjects receiving placebo or daily IR risedronate and in subjects receiving weekly or monthly IR risedronate compared to daily IR therapy. Upper abdominal pain occurred somewhat more frequently in the DR BB groups while slightly more subjects experienced diarrhea with the DR FB regimen, but these differences did not result in more subjects discontinuing from study medication. As expected, no cases of osteonecrosis of the jaw or atypical femoral fractures were observed in these subjects who received treatment for only 2 years. These data support the results of previous large studies that demonstrated good tolerability and short-term safety of risedronate therapy.
The number of subjects experiencing clinical fractures was very low, precluding the chance of observing differences among dosing regimens. Thus, it is unclear whether the greater effects of the DR regimen on bone mineral density and bone turnover, compared to IR daily dosing, would result in better fracture protection.
These 2-year results confirm that weekly administration of the 35-mg DR formulation results in changes in BMD and bone turnover that are at least as effective in increasing BMD and reducing bone turnover as the daily IR dosing regimen that is known to significantly reduce the incidence of fragility fractures in postmenopausal women with osteoporosis. A weekly dosing regimen that can be taken following breakfast is more convenient for many subjects with busy schedules or in older subjects who must take many other medications each morning. More importantly, the DR formulation of risedronate provides confidence to clinicians that poor compliance with dosing recommendations will be less likely to blunt the therapeutic effectiveness of risedronate.
Many factors influence the choice of a treatment for subjects with osteoporosis including confidence in anti-fracture efficacy, tolerability, individual subject circumstances affecting compliance, and persistence as well as subject preferences. Having an oral bisphosphonate that can be given following breakfast is a useful addition to our menu of treatment options.