Table 2.

Drug holiday studies

STUDYCOMPARATOR GROUPSLENGTH OF TREATMENT, YDRUG HOLIDAY, YFRACTURE CHANGES DURING DRUG HOLIDAY PERIODSURROGATE MEASURE CHANGES DURING DRUG HOLIDAY PERIOD
Watts et al,91 2008RIS vs PBO31

  • Previous RIS group (1-y holiday) had 46% lower risk of morphometric vertebral fracture (RR = 0.54, 95% CI 0.34 to 0.86) compared with previous PBO

  • Nonvertebral fractures were 5.0% in previous PBO group and 4.8% in previous RIS group (NS)

  • In the previous RIS group, BMD significantly decreased at the LS (−0.83%, 95% CI −1.30 to −0.35) and FN (−1.23%, 95% CI −1.87 to −2.19), but remained above baseline

  • BTM after 1 y returned to baseline levels

Black et al,53 2006ALN (10 y) vs ALN (5 y) then PBO (5 y)5 or 105

  • No significant differences between groups for all clinical fractures (19.9% with ALN, 21.3% with PBO; RR = 0.93, 95% CI 0.71 to 1.21)

  • No significant difference between groups for nonvertebral fractures (18.9% with ALN, 19.0% with PBO; RR = 1.0, 95% CI 0.76 to 1.32)

  • No significant difference between groups for morphometric vertebral fractures (9.8% with ALN, 11.3% with PBO; RR = 0.86, 95% CI 0.60 to 1.22)

  • Significant difference between groups for clinical vertebral fractures (2.4% with ALN, 5.3% with PBO; RR = 0.45, 95% CI 0.24 to 0.85)

  • Post hoc analyses demonstrated NS increases in the risk of clinical vertebral and nonvertebral fracture in those PBO patients with low baseline BMD or prevalent fracture

  • ALN mean TH BMD decline of 1.02% vs 3.38% for PBO (mean difference of 2.36%, 95% CI 1.81 to −2.90, P < .001)

  • ALN mean LS BMD increased by 5.26% vs 1.52% for PBO (mean difference of 2.36%, 95% CI 1.81 to −2.90, P < .001)

  • At all sites, BMD after 10 y of ALN therapy was significantly (P < .05) greater than for those given 5 y ALN and then PBO for 5 y

  • BTM in those who continued on ALN were unchanged, whereas those who started PBO after 5 y had a gradual rise in BTM during the following 5 y but always remained below pretreatment levels

  • Adverse events were similar between groups

Black et al,56 2012ZOL (6 y) vs ZOL (3 y) then PBO (3 y)3 or 63

  • No significant differences between groups for all clinical fractures (HR = 1.04, 95% CI 0.71 to 1.54)

  • No significant difference between groups for nonvertebral fractures (8.2% with ZOL, 7.6% with PBO; HR = 0.99, 95% CI 0.26 to 0.95)

  • Significant difference between groups for morphometric vertebral fractures (3.0% with ZOL, 6.2% with PBO; OR = 0.51, 95% CI 0.26 to 0.95)

  • No significant difference between groups for clinical vertebral fractures (HR = 1.81, 95% CI 0.53 to 6.2, NS)

  • ZOL mean FN BMD change of 0.24% vs −0.80% in PBO (mean difference 1.04%, P < .001)

  • ZOL mean LS BMD increased by 3.20% vs 1.18% for PBO (mean difference 2.03%, P < .01)

  • At all sites, BMD after 6 y of ZOL therapy was significantly (P < .05) greater than for those given ZOL for 3 y and then PBO for 3 y (except distal radius)

  • Serum N-terminal propeptide of type I collagen rose slightly in both the ZOL (19%) and PBO (33%) groups (P < .001), but remained substantially below pretreatment levels

  • Adverse events were similar between groups, but there was a significantly larger incidence of elevated serum creatinine > 0.5 mg/dL from baseline in the ZOL group (n = 18) compared with the PBO (n = 4) group (P < .01). All cases were transient and resolved without affecting renal function

  • ALN—alendronate, BMD—bone mineral density, BTM—bone turnover markers, FN—femoral neck, HR—hazard ratio, LS—lumbar spine, NS—not statistically significant, OR—odds ratio, PBO—placebo, RIS—risedronate, RR—relative risk, TH—total hip, ZOL—zoledronic acid.