Biomedical Engineering Reference
In-Depth Information
8 Combining Bisphosphonates and Teriparatide
Teriparatide will promote a significant improvement in bone mass and stimulation
of bone formation, even in those patients who have been pre-treated with other
drugs for years [
117
-
119
]. However, most of the evidence available suggests that
administration of bisphosphonates prior to teriparatide treatment [
95
], or concur-
rent administration of both [
97
,
120
], will impair or at least delay the full anabolic
response to PTH. In two landmarks studies [
97
,
120
], investigators found that bone
mineral density increased more in those given teriparatide alone, than in those
given both alendronate and teriparatide, although the combination treatment still
performed better than alendronate alone. These effects appear to last for at least
6-12 months [
95
,
121
]. This is not the case for all anti-catabolic agents; PTH's
effects are not blunted by prior administration with raloxifene, a selective estrogen
receptor modulator (SERM) [
95
,
122
] or by hormone replacement therapy [
123
].
Moreover, the blunting effect varies even among different BPs. Administration of
teriparatide for one year had a greater effect on bone formation, measured by
serum biomarkers, and BMD of the spine in patients treated previously for 2 years
with risedronate than in those treated previously with alendronate [
118
], with a
concomitant increase in predicted stiffness and failure load [
124
]. The difference
between effects with prior risedronate treatment compared to prior alendronate
treatment were apparent as early as 3 months following the initiation of teri-
paratide therapy [
118
]. These differences in PTH responsiveness among the BPs
are likely related to differences in their binding affinity.
The results from studies using animal models provide a mixed picture. There
was no effect of prior treatment with alendronate on trabecular bone formation in
ovariectomized rats [
125
], whereas others [
126
] do detect a suppression of skeletal
responsiveness to PTH following alendronate pretreatment. Again, the experience
with bisphosphonates that have different binding affinities varies in this regard.
A recent study in aged rats also showed that an 8 week period of risedronate
treatment blunted the stimulatory effect of subsequent PTH on bone remodeling
[
127
], but bone formation by PTH was not suppressed 10 weeks after withdrawal
of risedronate administration.
The blunting effect of bisphosphonate pre-treatment on PTH stimulation of
bone formation may diminish over treatment time. In the EUROFORS study, the
initial significant delay in the increase of BMD [
128
], as a surrogate for bone
formation, in the group treated with alendronate, was completely reversed
following 2 years of PTH therapy, resulting in a significant increase in BMD
[
117
,
129
]. Using iliac crest biopsies, Stepan et al. similarly found no difference in
bone formation rates following 19 months of teriparatide treatment between those
who were previously treated with alendronate for 5 years, and those who were not
previously treated [
119
]. The microdamage accumulation caused by remodeling
suppression was reversed by subsequent administration of teriparatide, and those
patients with the lowest BMD had the greatest removal of microdamage [
115
].
Although this study was not able to conclude that a change in bone turnover rate
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