what-when-how
In Depth Tutorials and Information
A
NABOLIC AGENTS AND O
I
also been studied and shown to have positive effects on
vertebral bone mineral density in women with severe
osteoporosis, but is not currently approved for use in
the United States.
39
Importantly, the use of parathyroid
peptides is contraindicated in children because of uncer-
tainty of the effects on skeletal growth and lack of safety
data. Moreover, duration of teriparatide treatment is cur-
rently limited to two years because of early toxicology
studies that showed an increased risk of osteosarcoma in
rodents treated for prolonged periods.
These results and the hypothesized mechanisms of
action (bone formation) suggest that teriparatide treatment
may be useful in adults with OI. Poor osteoblast function
seen in OI may benefit from an anabolic agent. However,
anabolic agents will not address the underlying collagen
defect, and as OI is a condition of poor bone quality in
addition to decreased quantity, the potential production
of additional undermineralized bone could conceivably
result in worse outcomes such as increased fractures or
bone pain. Trials are currently under way examining the
effectiveness of teriparatide in adults with OI.
Recombinant Parathyroid Hormone
Teriparatide (human recombinant parathyroid hor-
mone (hrPTH 1-34)) is a pharmacologic intervention
that is well studied for the management of osteoporosis
in postmenopausal women and men.
37-42
Parathyroid
hormone (PTH) is an 84 amino acid peptide hormone
produced in the parathyroid glands, with the biologic
purpose of maintaining adequate circulating serum cal-
cium levels. The medication is delivered in pulsatile dos-
ing, and the intermittent exposure activates osteoblasts
to a greater extent than osteoclasts.
43,44
While the exact
mechanism is still unclear, the result of daily teriparatide
injections, unlike with anti-resorptive medications such
as bisphosphonates, is a net anabolic effect and new bone
formation. As osteoblasts are activated, they produce
both RANKL, which stimulates osteoclast activation
and bone resorption, and osteoprotegrin (OPG), which
competitively inhibits RANKL. Locklin et al. show that
with cyclical administration, the RANKL/OPG ratio is
reduced, producing a hypothesis that the observed ana-
bolic effect with cyclical administration may be due to
decreased RANKL action.
45
Teriparatide therapy has also been show to have other
potentially beneficial effects. It increases c-fos expression,
a transcription factor observed at highest levels during
osteoblast proliferation. Teriparatide has been associ-
ated with the recruitment of mesenchymal stem cells to
the bone surface in mouse models, to potentially inhibit
apoptosis of osteoblast cells, and to decrease sclerostin
levels enabling Wnt signaling for osteoblast prolifera-
tion.
46
Studies of teriparatide in osteoporosis have also
demonstrated a possible effect on periosteal deposition,
with resulting increases in cortical volume, cortical thick-
ness and cross-sectional area.
37,39-41,47,48
In women at high risk of fracture, treatment with
20 mcg doses of teriparatide resulted in prominent
increases in BMD at the lumbar spine, but lesser
increases at the proximal femur and actual reductions in
areal BMD at the radial measurement sites. Nevertheless,
treatment resulted in a 65% reduction in the risk of one
or more vertebral fractures and a risk reduction of 35%
for nonvertebral fracture. Those treated with 40 mcg
doses had slightly higher fracture risk reduction, but
increased side effect risk.
37
In men age 30-85 with osteo-
porosis, 20 mcg teriparatide increased spine BMD by
5.9%, femoral neck BMD by 1.5%, and similar to studies
in women, no significant increase was observed in the
distal radius.
47
The most commonly reported adverse
effects in these studies were nausea and headaches. In
osteoporosis, the improved BMD in the femoral neck has
been observed for up to 30 months following discontinu-
ation of treatment.
48
The full length hormone PTH
1-83
has
Sclerostin Antibodies
Sclerostin is a glycoprotein encoded by the SOST gene
and produced in osteocytes.
49-51
Mutant SOST genes
have been identified in the condition sclerosteosis, which
is characterized by progressive thickening of bone.
52,53
Sclerostin is an inhibitor of the Wnt/β-catenin signaling
pathway, which stimulates osteoblast differentiation and
bone formation.
50,51,53-55
When sclerostin is reduced the
remodeling process is uncoupled, resulting in net bone
formation.
55,56
AMG 785 is a humanized monoclonal
antibody to sclerostin which completed phase 2 clinical
trials in 2011 and initiated phase 3 clinical trials in April
of 2012.
57
In preclinical trials, treatment with sclerostin antibod-
ies completely reversed estrogen deficiency-induced
bone loss in rats, with both greater bone mass and
strength observed after treatment.
56
Accelerated repair
of fractures and increased bone strength at the site of
fracture in rodents and non-human primate studies may
translate into important implications for OI.
53
In clinical trials in healthy men and postmenopausal
women age 45-59, a dose-dependent increase in bone
formation markers P1NP, BAP and osteocalcin were
noted with both intravenous and subcutaneous admin-
istration.
58
Improvements in BMD of the lumbar spine
and total hip were also observed with a 5.3% increase
in lumbar spine BMD and 2.8% increase in total hip
BMD noted at day 85 of treatment in subjects receiv-
ing 10 mg/kg AMG 785 given subcutaneously.
58
Phase
3 trials commenced in April of 2012 in postmenopausal
women with osteoporosis.
59
Since inadequate bone
formation is a major problem in OI, drugs that reduce
