Endpoints of the FACT study. The primary endpoint was change from baseline BMD at the hip trochanter at 12 months. Secondary endpoints included BMD at multiple sites, bone turnover markers, and drug tolerability. After 12 months, BMD increased 3.4% with alendronate and 2.1% with risedronate (P<.001 alendronate produced significantly greater reductions in bone markers. fracture data were collected as part of the safety monitoring: fractures group and risedronate group.>
Antiresorptives lower fracture risk even without increasing BMD
However, until a head-to-head antifracture efficacy study is done, we cannot infer whether alendronate or risedronate is more effective, based on surrogate endpoints. In fact, if one looks at observations on calcitonin and raloxifene, all 4 drugs provide a similar level of fracture protection, at least in the spine, despite marked differences in turnover markers and BMD. This similarity in antifracture efficacy is probably because antiresorptive drugs affect bone quality and microarchitecture, as well as bone mass.
Antiresorptive medications reduce fracture risk, even in the absence of substantial increases in BMD. This finding has significant implications for monitoring therapy. The misconception that efficacy depends on the amount of bone gained often prompts physicians to stop a drug or add a second drug if a patient’s bone density does not increase. The indication of treatment success, however, is absence of bone loss, not extent of bone gain.
The key to meaningful monitoring
Serial observations with DEXA scanning are fraught with error if one does not understand the concept of least specific change. Least specific change is defined as 2.77 times the precision error of the scanning machine used. Thus, in good centers, BMD measurement of the spine should vary no more than ±3%; measurement of the hip may vary as much as ±5%. For example, a patient who gains 2% over time in the hip and spine is no different statistically from a patient who loses 2% over time in the hip and spine. However, many patients and clinicians feel gratified by a modest increase—and consider an alternative or additional medication if there is a mild decrease. If we take into account the “least specific change,” it becomes evident that in both cases, the patients are in fact unchanged.
Daily pill more likely to get blamed for GI symptoms?
The perception among many clinicians prior to the FACT head-to-head trial was that risedronate had greater GI tolerability than alendronate. However, in the FACT trial no differences were noted in adverse events of the GI tract for either compound. When first introduced, alendronate was a daily regimen. Both alendronate and risedronate are now being given once per week, predominately, and it seems that this schedule has led to fewer complaints and fewer patients discontinuing medication because of GI symptoms. This change probably is because patients are not as likely to relate all of their GI symptoms to a pill taken a week ago, but are more likely to blame any GI complaint on a pill they take every day.
ADDITIONAL REFERENCES
- Bauer DC, Black DM, Garnero P, et al for the Fracture Intervention Trial Study Group. Change in bone turnover and hip, nonspine, and vertebral fracture in alendronate-treated women: the Fracture Intervention Trial. J Bone Miner Res. 2004;19:1250–1258.
- Watts NB, Cooper C, Lindsay R, et al. Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom. 2004;7:255–261.
Which is better, once-a-month or once-a-day ibandronate?
Miller PD, McClung MR, Macovei L, et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res. 2005;20:1315–1322.
- “Monthly ibandronate is at least as effective and well tolerated as…the daily ibandronate regimen in postmenopausal osteoporosis.”
Which schedule will patients follow?
Virtually all clinicians would agree that patients prefer weekly to daily dosing, especially if the medication is somewhat inconvenient. Bisphosphonates should be taken with a full glass of water, and the patient should remain standing or sitting upright and avoid other food or drink for 1/2 hour (a full hour with ibandronate).
It remains to be seen. Once-a-month dosing may offer more appeal than weekly alendronate or risedronate, but whether adherence will be better or worse remains to be seen.
Does ibandronate prevent fractures?
Daily ibandronate, 2.5 mg, has been shown to improve bone density and bone turnover values and to reduce vertebral fractures.