what-when-how
In Depth Tutorials and Information
targeting to bone, and there are recent reviews of safety
aspects.
18,20
There is no evidence of teratogenicity when
any of the compounds are administered during preg-
nancy; infants conceived either to mothers still receiv-
ing or who previously received these drugs have shown
no evidence of any abnormality of the skeleton either at
birth or subsequently during growth.
21
Gastrointestinal irritation has been reported in older
women receiving oral bisphosphonates as treatment for
post-menopausal osteoporosis.
22
Although such effects
can be produced in animals, the mechanisms in humans
are not clear; reflux may play a part, but there may also
be direct irritant effects on the mucosa.
23
Data for older
individuals with OI are sparse;
24
the drugs seem well tol-
erated in the reports of therapy in the pediatric age group
with little or no difference in adverse events between
groups in placebo-controlled trials,
25-28
but most of the
original reports of bisphosphonate use in the PMO group
reported good tolerability. There is still some continu-
ing debate over the relative tolerability of the two most
widely used oral drugs, alendronate and risedronate, with
fewer endoscopically confirmed erosions for risedronate-
treated patients in a prospective study of daily therapy.
29
Tolerability towards nitrogen-containing bisphosphonates
is generally held to be better with less frequent adminis-
tration and most dosing regimens are now weekly or even
less frequent. In confirmation of this approach, a head-to-
head comparison of weekly treatment with alendronate
and risedronate in over 1000 patients showed no differ-
ence in upper GI symptoms or outcomes.
18,30-31
Concerns have been raised over the possibility that
long-term exposure to oral bisphosphonates could
increase the risk of esophageal cancer. However, there is
no conclusive evidence of a link, and indeed gastric and
colon cancers may even be reduced in bisphosphonate
users.
18,31
In addition, physicians using bisphospho-
nates should be aware of a possible risk of neoplasia,
which should lead to early referral and appropriate
investigation in patients who present with signs that are
consistent with esophageal cancer.
A variety of eye-related inflammatory complications
have been reported over the years, typically affecting
less than 1% of patients. Bisphosphonates should be used
with caution in those with a history of inflammatory eye
problems. Treatment of such a problem is cessation of
bisphosphonate therapy and in some cases a short course
of corticosteroids. Ophthalmic review should be sought.
Among other adverse events much media and medi-
cal attention has been given to the possible association
with osteonecrosis of the jaw (ONJ) and subtrochanteric
atypical femur fractures (AFFs). These are rare events,
which have not been seen in excess in appropriately
controlled prospective clinical trials. For both entities,
the American Society of Bone and Mineral Research has
produced consensus reports including case definitions.
Despite much speculation a causal relationship has not
been established for either ONJ or AFFs. Nonetheless
for ONJ, preventive measures in at-risk adults include
the completion of dental work prior to bisphospho-
nate therapy where practical, and the early treatment of
any dental infections. It is recommended that implants
should be avoided if possible.
ONJ is extremely rare in non-cancer patients, but does
occasionally occur in cancer patients, especially after
tooth extractions or other dental procedures, and the
overlap with osteomyelitis is often confused. ONJ has
been reported in patients receiving head and neck radio-
therapy and has also been reported with the use of deno-
sumab, a resorption inhibitor that blocks RANK-ligand,
32
but again only in patients with cancer. ONJ has not been
reported in children or young adults up to age 25 despite
the high doses of bisphosphonate treatment (on a per
kilogram bodyweight basis) often given to children with
OI. Moreover, in a large series of dental procedures in
children no cases of ONJ were encountered.
33
Both in benign and oncology settings, the overall ben-
efits of bisphosphonate therapy have consistently out-
weighed their potential risks. Bisphosphonates improve
the quality of life in patients with metastatic bone cancer
and delay the development of adverse skeletal effects.
In respect of atypical femoral fractures, there are five
major criteria that are all required for the case definition
to be met. These are:
1.
The site of fracture - distal to the lesser trochanter to
proximal to the supracondylar flare/widening
2.
Cortical involvement - if single cortex only, then this
must be the lateral cortex
3.
Fracture orientation - transverse or minimally oblique
4.
The degree of trauma - none, or minimal
5.
Severity - not comminuted
Such fractures do occur occasionally in other patient
groups and similar fractures have been reported in chil-
dren with OI, including those without bisphosphonate
exposure.
Atrial fibrillation was reported as increased in the
treatment group of the initial HORIZON study of zole-
dronic acid in PMO; however, the results were not rep-
licated in the recurrent fracture arm of the study (where
patients were older). It has not been possible to estab-
lish whether other bisphosphonates might also increase
the risk of arrhythmias as the data were not collected
accurately at the time of the RCTs that showed their
anti-fracture efficacy. Case-control and cohort studies
in the USA and Europe have yielded conflicting results.
Although atrial fibrillation has been added to the label
of both pamidronate and zoledronic acid as a possible
side effect, clear evidence for such an effect is lacking.
There have been no reports of arrhythmias in associa-
tion with bisphosphonate use in OI.
