Bisphosphonates and PTH for Preventing Fractures - Skeletal Aging and Osteoporosis: Biomechanics and Mechanobiology - page 154

those previously treated with alendronate [ 17 ]. Animals treated with clinically
relevant doses of either risedronate or alendronate for 8 weeks and assessed
16 weeks after discontinuation of treatment, show a return to control values in
risedronate treated animals but not in alendronate treated animals. These differ-
ences in recovery of remodeling following treatment withdrawal were ascribed to
differences in binding affinity.
Differences in binding affinity, and in potency, may also be reflected in how
quickly initial administration of bisphosphonates begin to have their effects.
Recent data shows that the incidence of non-vertebral fractures and the incidence
of hip fractures in the first year on therapy is significantly lower in risedronate-
treated patients than in alendronate-treated patients [ 43 ]. This concept was recently
addressed in an animal model in which, as early as three weeks after the initiation
of treatment with clinically relevant doses, vertebral bone remodeling was sup-
pressed to a significantly greater degree in risedronate-treated animals than
alendronate-treated animals. All BPs have a semi-unique remodeling suppression
fingerprint and this likely plays a role in their clinical efficacy.
3.3 Long-Term Suppression of Remodeling
The high affinity of BPs for bone mineral, and their long-term retention in bone,
are of some concern because continued accumulation of BPs, or continued sup-
pression of remodeling over prolonged treatment periods could eventually increase
the risk of fracture, even in the face of increased bone mass. The seven-year
alendronate clinical trial data show an increase in the annualized incidence of new
vertebral fractures rates in years 6 and 7 compared to baseline placebo group
fracture rates. In the first three years of the clinical trial [ 44 ], the placebo group
sustained an annualized vertebral fracture incidence of 2.1%, compared to 0.9% in
the alendronate treated group. During years 6 and 7 of the two year extension
study, the alendronate treated group sustained an annualized vertebral fracture
incidence of 3.3%, more than 50% greater than the incidence of vertebral fractures
in the placebo group at the beginning of the study [ 45 ]. This is not an exact
comparison because of differences in methods of assessing vertebral fractures, the
absence of a placebo control in years 6 and 7 (due to ethical considerations once
efficacy is shown), and the fact that the mean age of the women in the extension
study was undoubtedly older than at the initiation of the trial, although the mean
age is not reported in the extension study. This raises concerns that long-term
treatment with BPs could ultimately be detrimental to the health of the patient.
Recently, several groups have reported an apparent increase in the incidence of
atypical femoral fractures, especially in the population of osteopenic women who
are being treated for osteoporosis with alendronate for an average of 4-8 years
[ 46 - 49 ]. Although epidemiologic data on atypical femoral fractures is not
extensive (and the terminology used to describe femoral fractures is often con-
fusing and inconsistent), low energy subtrochanteric fractures are not infrequent in