Discussion
Bisphosphonates are manifestly effective in the treatment of
osteoporosis in adults by inhibiting osteoclast-mediated bone
resorption. Experience in children with low bone mineral is less
extensive but generally supports the same
conclusion.19 This is exemplified by a report on a
small number (n=22) of children with a variety of chronic illnesses
associated with loss of bone mineral, none with malignant
disease.31 In a randomized clinical trial (RCT) the
participants received either oral alendronate weekly or placebo for one
year. Volumetric bone density of the lumbar spine increased
significantly in the experimental group but not in those receiving
placebo. Likewise, the cross-sectional moment of inertia per unit length
of the femoral shaft - an estimate of mechanical strength - increased
significantly only in the experimental group.31
A recent report from the Cincinatti Children’s Hospital Medical Center
is of a 7 year retrospective chart review describing the outcomes of
intravenous bisphosphonate infusions in patients less than 21 years of
age.32 Among the patients who were excluded were all
of those (N=12) who had received cancer chemotherapy, but 29 of the
study sample (N=123) were categorized as having glucocorticoid-induced
osteoporosis. In the 42 patients who had at least two DXA examinations
available for comparison there was a significant gain in LS aBMD) at one
year after bisphosphonate infusion.
In the non-randomized study reported here, involving only children with
ALL (n=68) on active therapy who received oral alendronate weekly for a
shorter time than in the RCT reported by Rudge et
al.,31 LS aBMD increased significantly as measured by
Z score with and without HAW correction. The sequential results from DXA
examinations are indicative of a short-term gain in LS aBMD from the
administration of alendronate, blunting an otherwise downward
trajectory. These changes occurred at an age when bone mass is
increasing in healthy children, adolescents and young adults. In a
population of healthy Caucasian subjects in Ohio, who were studied
serially by DXA between the ages of 8-30 years,33 the
rate of accumulation of bone mass began to slow in mid to late teens in
females (N=343) with peak BMD attained in the early 20s, while in males
(N=312) the corresponding rate began to slow in late teens to early 20s
with peak BMD attained by mid to late 20s. Comparable Canadian data have
been reported.34 Achieving a normal peak bone mass by
age 30 is important in the prevention of osteoporosis in older adult
life.35 Consequently, rendering the subjects in this
study osteopenic from the treatment of ALL, despite a temporary and only
partial reprieve by the administration of alendronate, has put them at
risk of fragility fractures in later life. In a separate study from our
centre,36 LS aBMD during maintenance/continuation
therapy of ALL was shown to be predictive of later fractures in children
who did not receive a bisphosphonate. The results in the small number of
subjects (n=9) reported here, who were studied more than a decade after
diagnosis, are intriguing, being suggestive of late improvement in LS
aBMD, but longitudinal examination of a larger cohort will be required
to evaluate this observation. A recent Dutch-Canadian collaborative
study has demonstrated the predictive value of age and weight at
diagnosis in relation to LS aBMD and to subsequent development of
symptomatic fractures in children with ALL,37complementing our established practice of HAW correction of Z scores for
aBMD of the lumbar spine.28
The results of bone morphometry and measures of bone strength,
determined by peripheral quantitative computed tomography
(pQCT)38 in our study of long term survivors of ALL
(more than 10 years from diagnosis), have been reported
separately.39 There were no statistically significant
differences in any of 19 metrics between those who had received
bisphosphonate (n=14, pamidronate in 5) and those who had not (n=58).
This may represent adaptive restructuring of trabecular bone by
thickening of a reduced number of trabeculae to maintain bone
strength.40 Again, the improvement in LS aBMD
following discontinuation of long-term steroid therapy has been reported
in young adults with sarcoidosis.41
There have been few prior studies of bone by pQCT in children with ALL.
Brennan et al. in the UK reported on 53 survivors on average almost 5
years after completion of treatment which did not include cranial
radiation.42 There was no deficit in LS aBMD but
reduced BMD in the trabecular bone of the distal radius was revealed.
More recently, a group of 50 survivors in the US were studied within two
years of completing treatment without cranial radiation, and again one
year later.43 A large group of healthy subjects
afforded the provision of Z scores. Initial deficits were shown in both
trabecular and cortical BMD in the tibia. Subsequent changes in the
cortical outcomes varied by the duration of the interval since
completion of therapy. Interestingly, there were no associations of the
outcomes with leukemia risk category, total glucocorticoid dose or
antimetabolite therapy.
With respect to the short-term safety of oral alendronate, this has been
assessed in detail in randomized clinical trials conducted in young
people. In a study of 32 adolescents with anorexia nervosa who received
the drug or placebo daily for one year, the authors stated ”We found
alendronate to be well tolerated and safe”.44 A more
recent trial in 139 children with osteogenesis imperfecta, involving
daily oral alendronate for two years, prompted the authors’ observation
”Importantly, ALN was associated with few adverse events. In particular
gastrointestinal symptoms were not more common in patients receiving ALN
than in those receiving placebo”.45 In a systematic
review of bisphosphonates in children and adolescents with secondary
osteoporosis Ward and colleagues noted that oral alendronate appeared to
be well tolerated for intervals up to 3 years.46 A
report of the use of oral alendronate in post-menopausal osteoporosis
stated that the drug was efficacious and well tolerated over a 10 year
period.47 In our non-randomized study gastrointestinal
symptoms were infrequent and minor in degree, with one exception, and no
other adverse sequelae were recorded. The retrospective study by
Nasomyont and colleagues32 determined that “In 468
patient years of bisphosphonate exposure there were no reports of ONJ
(osteonecrosis of the jaw) or AFF (atypical femoral fracture) in medical
record.” In a systematic review published in 2020 no cases of ONJ in
children were identified.48
The other safety issue addressed in our study is that of the
relationship of bisphosphonates to the risk of cancer, in this instance
relapse of ALL. We are not aware of this having been studied previously
in children. By contrast, it has been a topic of considerable interest
in the context of adults. Pre-clinical data and some, but not all,
clinical trials suggest an anti-neoplastic effect of
bisphosphonates.49 A recent study using murine models
of ALL showed a significantly shorter survival in animals receiving
zoledronic acid, a third generation bisphosphonate, as well as
chemotherapy compared to those receiving chemotherapy alone, but this
was not seen using xenografts of human B precursor and T cell
ALL.50
A large study in the UK, using data extracted from the General Practice
Research Database, examined 41,826 subjects who had been exposed to oral
bisphosphonates and an equal number of matched
controls,51 investigating the risk of developing
cancer overall as well as specific neoplasms. It was reported that there
was a significant protective effect in general and specifically in
relation to breast and colorectal cancers. No such effect was evident
for leukemias and lymphomas, but in no instance was the risk of cancer
increased. In comparison, the results of a population-based cohort study
in South Korea, using the National Health Insurance Services database,
showed no association between exposure to oral alendronate or
residronate and the risk of breast, ovarian or cervical
cancer.52 This study involved 14,847 users and 204,525
unmatched controls.
A systematic literature review of the prognostic effect of
bisphosphonate exposure in adult patients with a solid tumor found
improved overall survival as well as cancer-specific and recurrence-free
survival.53 For individual cancer types there was an
apparent benefit in overall survival for patients with gastro-esophageal
cancer and longer cancer-specific survival in those with breast cancer.
In a separate study, exposure to alendronate was associated with a lower
risk of bone metastases in osteoporotic women with breast
cancer.54
Against this background our finding that there was no increased
frequency of relapse in children receiving oral alendronate while
undergoing active therapy for ALL may offer a measure of reassurance.
Whether there was a protective effect is intriguing – the proportion of
patients who relapsed after receiving alendronate was less than 50% of
that in those who did not receive the drug, and more patients who
received alendronate had high risk disease - but cannot be addressed
with confidence. However, in a recent report,55 B cell
ALL cells were shown to mediate resorption of trabecular bone by a
RANK-RANKL (receptor activator of nuclear factor kB ligand) mechanism
through activation of osteoclasts. The authors postulated that combining
an anti-resorptive agent with chemotherapy may reduce the risk of
relapse by disrupting this B cell activity.
This was a retrospective cohort study with a small number of patients.
Other limitations are the variability in the duration of alendronate
administration, although this reflects variation in the timing of
responsiveness to this medication, and the lack of reliable information
on fractures. A much larger longitudinal study with well-matched
controls, perhaps in the form of a randomized trial to examine the
efficacy of a bisphosphonate in osteopenic children with ALL, would be
valuable.
Conflict of Interest statement. The authors have no conflicts of
interest to declare
Acknowledgements. We acknowledge the contributions of Jo-Ann Fowler BScN
and Sarah Beasley BScN to the collection of data from clinical records.
Figure legend. Sequential lumbar spine bone mineral density Z scores in
children and adolescents with acute lymphoblastic leukemia who received
alendronate.