what-when-how
In Depth Tutorials and Information
sclerostin action may be of benefit for increasing bone
mass and strength. Of course, this approach would not
address the primary molecular defect in OI, and the
benefit and drawbacks of stimulating new but abnor-
mal bone formation in OI are unknown, either in chil-
dren or adults.
denosumab administered subcutaneously twice yearly
for a total of 36 months was shown to reduce the risk of
vertebral fractures from 7.2% to 2.3%, to reduce the risk
of hip fracture from 1.2% to 0.7% and to reduce the risk
of nonvertebral fracture from 8.0% to 6.5%.
64
Potential
risks of use include dermatitis, infection, hypocalcemia.
Recently, osteonecrosis of the jaw has been reported in
conjunction with denosumab treatment.
64
This evidence showing reduced bone turnover and
improved BMD suggests this may be a potential medica-
tion for trial in OI. Studies have reported on use of deno-
sumab in mouse models of OI.
68,69
A trial of recombinant
murine RANKL inhibitor on healing and strength follow-
ing osteotomy in mouse models of OI revealed no delay
in healing, and increased strength was noted in intact
bone following treatment.
68
No change in fracture rate
was seen in a subsequent study using murine analogs of
human RANKL inhibitors after 2 weeks of treatment, but
increased metaphyseal density and bone strength were
reported.
69
More recent studies report a similar reduc-
tion in fractures in OI mouse models as that seen with
alendronate treatment.
70
To date, these trials support the
potential for future clinical trials of denosumab in OI.
Strontium Ranelate
Strontium ranelate, consists of two cations of strontium
and organic ranelic acid. Although the specific mecha-
nism of action of strontium ralenate remains unclear
it appears to have dual anabolic and anti-resorptive
action on bone resulting in increased bone density and
cortical thickness, and is currently approved for use in
treatment of osteoporosis outside of North America.
60
Given high rates of bone turnover seen in OI in combi-
nation with poor mineralization, this dual action may
have a beneficial effect. Clinical trials in postmenopausal
women with osteoporosis have demonstrated a dose-
dependent increase in BMD.
61,62
Three years of treatment
resulted in a 41% reduction in vertebral fracture risk, with
lesser reductions observed in non-vertebral fractures.
62
Given high rates of bone turnover with poor mineraliza-
tion in OI, the dual action of strontium ranelate may have
a beneficial effect, but trials have not yet been reported.
Adverse effects linked to strontium, including thrombosis
and systemic immune reactions, warrant consideration
prior to trials in OI.
63
Cathepsin K Inhibitors
Cathepsin K is a cysteine protease with type I and
type II collagenase activity that is predominantly
expressed by osteoclasts.
71
It is secreted into the resorp-
tion lacunae below active osteoclasts resulting in type I
collagen degradation.
71
The expression of cathepsin K
is upregulated by RANKL.
72,73
The congenital absence
of cathepsin K results in the condition pycnodysosto-
sis, where high volumetric bone density is observed.
74
In preclinical trials, inhibitors of cathepsin K reduced
bone resorption biomarkers and increased bone mineral
density in rabbit and non-human primate models.
75,76
Odanacatib is one such selective cathepsin K inhibitor
currently in phase 3 clinical trials.
In primates receiving treatment with odanacatib,
dose-dependent decreases in bone resorption and
increases in BMD were observed, with increases in peri-
osteal formation and bone strength.
77-79
Similar effects
have been noted in 2-3 year trials in postmenopausal
women.
77,80
Of interest, biochemical indices of remode-
ling suggest that odanocatib induces relatively more
suppression of bone resorption than bone formation,
whereas all remodeling indices are markedly reduced
with bisphosphonate therapy. While resorption bio-
markers were suppressed for the first two years of treat-
ment in postmenopausal women, they returned to near
baseline levels in the third year of treatment in the face
of continued increases in BMD.
77
Discontinuation of
treatment resulted in a loss of BMD during the following
year, corresponding with an increase in bone resorption
ANTI
RESORPTIVE AGENTS AN
D OI
RANK-Ligand Inhibitors
Expanded knowledge about the molecular pathways
underlying bone formation and remodeling includes rec-
ognition of the role of RANK-ligand. The RANK-ligand
cytokine is involved in binding and activating the RANK
receptor on osteoclast precursor cells, resulting in osteo-
clast activation and bone resorption.
46
Targeting this
mechanism for pharmacologic intervention resulted in
the development of RANK-ligand inhibitors including
denosumab, a human monoclonal antibody that revers-
ibly binds to and inhibits RANK-ligand.
64
In the randomized, double-blinded, placebo-controlled
clinical trial of denosumab in postmenopausal women,
an 81% decrease in C-telopeptide marker was observed
in treated women, with an increase in lumbar spine BMD
from 3.0% to 6.7% over 1 year.
65,66
In postmenopausal
women, a dose of 60 mg every 6 months for a total of 1
year was shown to increase lumbar spine BMD by 6.7%
relative to a loss of 0.6% in the placebo group, and the
effect was sustained for 12 months following the trial.
67
In a later study of women aged 60-90 with osteoporosis,
