Results
Within the sample, the age range was 1 to 18 median 4 years (mean 5.7, SD 4.3) at the time of diagnosis and the M:F ratio was 116:101 (1.15). The majority had standard risk disease and almost 80% remain in continuous remission (Table 1). The interval from diagnosis to December 31, 2020 was 5.7 to 21.1 median 14.7 years (mean 14.5, SD 4.2).
The recipients of alendronate (n=69, 32%) were 1 to 18 median 6 years (mean 7.0 SD 5.2) of age at diagnosis and the M:F ratio was 37:32 (1.19). In the group who received alendronate 41% had high risk disease compared to 35% in the other group. Alendronate was administered for a mean (SD) of 87.1 (67.3) weeks; median 77, range 4 to 387 weeks. Two subjects were excluded from this analysis of duration of administration; one with Noonan syndrome received the drug for 6.5 years on the advice of an endocrinologist and another received prescriptions for 7.5 years but was felt to be largely non-compliant and had a LS aBMD Z score after this interval of -2.0. Both subjects were retained in the analysis of efficacy. LS aBMD prior to administration in the entire group of recipients is shown in Table 3.
SAFETY: Our experience with IV pamidronate in children with ALL has been reported.10 The side effects, including hyperpyrexia, were such that we abandoned the use of this agent. Alendronate was tolerated well overall and adherence was very high as a result of the schedule of administration. None of the participants experienced an acute phase reaction and only a few reported mild and short-lived gastrointestinal symptoms which did not interfere with compliance. However, one subject was truly intolerant, with symptomatic esophagitis, and so was withdrawn from further analyses.
Among those who received a course of alendronate, 7/68 (10.3%) relapsed, none during chemotherapy, of whom two died compared to 19/89 (21.3%), four during post-induction chemotherapy with four deaths, in those who did not receive the drug and were not lost to follow up. The difference in relapse rates is not statistically significant (p=0.06). An additional child who received alendronate was diagnosed with ALL 16 years after the original diagnosis. The phenotype was demonstrably different from that of the primary disease and so the new disease was deemed to be a second cancer, recognizing that this is a rare event.29,30
EFFICACY
The interval from completion of the course of alendronate to the next DXA examination was a mean (SD) of 100.5 (86.5) weeks; median 79, range -30 to 465 weeks. One subject’s last DXA was 6 months before finishing alendronate. The LS aBMD following alendronate is shown in Table 3 and represents a statistically significant increase, whether expressed as Z score (mean gain 1.31, p<0.0001) or HAW corrected Z score (mean gain 0.90, p<0.0001). While most of the subjects - 44/68 (65%) – still had negative Z scores, the majority (85%) gained BMD and 50/68 (74%) were within the normal range of -1.0 to +1.0. The correlation between duration of alendronate administration and the size of the gain in BMD was not statistically significant (r=0.017, p=0.891, nor was the correlation between the interval from completion of alendronate to next DXA examination and the size of the gain in BMD (r=-0.122, p=0.327).
A subgroup of 32 subjects had further DXA examinations, as part of their long term follow up, 5-9 years after finishing alendronate. Twenty-two of them (69%) still had negative Z scores although only half of those were osteopenic (LS aBMD Z score < -1.00). The results of the sequential DXA examinations on this subgroup are shown in Table 4 and Figure 1. The gains in BMD between time points 1 and 2 and between time points 1 and 3 were highly statistically significant (p<0.0001), but there was no significant difference in BMD between time points 2 and 3 (p=0.090). There was no relationship of Z scores or changes in Z scores to age or sex. Nine subjects had further scans more than 10 years from diagnosis as part of a cross-sectional study of long-term survivors; 8 had higher BMD Z scores than prior to receiving alendronate and only one was still osteopenic with a score of -1.6.