Clinical evaluation of novel bisphosphonate dosing regimens in osteoporosis: the role of comparative studies and implications for future studies.
BACKGROUND
Daily nitrogen-containing bisphosphonates have shown antifracture efficacy in many studies of postmenopausal osteoporosis. However, current dosing schedules are often inconvenient or impractical for patients. Efforts to reduce dosing frequency to improve adherence (ie, compliance and persistence), and therefore treatment outcomes, are ongoing. Although a number of trial designs can be used to consider the efficacy of therapy, comparing the efficacy of different regimens should only be undertaken in purposefully designed head-to-head studies.


OBJECTIVE
This article summarizes the design and conduct of clinical studies that have investigated alternative bisphosphonate regimens and those that have directly compared different approved bisphosphonates. It also explores the implications for future studies of postmenopausal osteoporosis treatment.


METHODS
Using the terms bisphosphonate, daily, weekly, and monthly, a search (completed in 2006) of the PubMed database was conducted to identify primary English-language publications of pertinent studies comparing either novel with established regimens of the same bisphosphonates or different established bisphosphonates.


RESULTS
The first option is the equivalence or noninferiority bridging study for comparison of new treatment regimens versus the established regimen of the same bisphosphonate, known as the active comparator. Four such studies have led to the registration of novel bisphosphonate dosing regimens designed to provide easier dosing alternatives for patients. The second option is the active comparator study, which compares one bisphosphonate with the most prescribed weekly bisphosphonate. Weekly dosed oral alendronate has previously been shown to be superior (for bone mineral density gains) to daily and weekly dosed oral risedronate. An ongoing noninferiority study, Monthly Oral Therapy with Ibandronate for Osteoporosis Intervention, is comparing weekly alendronate with ibandronate, a monthly oral bisphosphonate.


CONCLUSIONS
The exploration of new dosing schedules and formulations aims to identify the optimal bisphosphonate regimen for postmenopausal osteoporosis. To achieve this, careful consideration must be given to the choice of a scientifically valid study design that effectively, and ethically, meets the study objectives. Given the concerns regarding placebo-controlled antifracture studies, 2 alternative study designs should be considered, both using validated surrogate end points (bone mineral density and biochemical markers of bone turnover) as the principal mode of assessment.
Cosman
Felicia
F
Helen Hayes Hospital, West Haverstraw, New York 10993, USA. cosmanf@helenhayeshosp.org
Borges
Joao L C
JL
Curiel
Manuel Diaz
MD
D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000379:methods / Q000639:trends; D004164:Diphosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004341:Drug Evaluation / Q000379:methods* / Q000639:trends*; D005260:Female; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
D050071:Bone Density Conservation Agents; D004164:Diphosphonates