what-when-how
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the influence that inclusion in a structured clinical pro-
gram may have in determining treatment outcomes. For
example, inclusion in the study could have resulted in
improved vitamin D and calcium intake or alterations
in activity could have lessened fracture risk. The mar-
ginal increase (
p
= 0.06) in the post- to pre-treatment
ratio of fractures for pamidronate-treated patients com-
pared to non-treated patients requires a larger number
of observations to confirm or refute the possibility that
treatment in type I patients might have increased rather
than decreased fracture incidence. While this study
provided information about the BMD and fracture
response of OI adults to bisphosphonate treatment, it
did not conclusively answer the question as to whether
adult OI patients should be treated with bisphospho-
nates. Certainly the response in adults differs from that
in children, and this should be incorporated in the clini-
cal decision as to whether bisphosphonate treatment is
appropriate for an individual patient.
43
Bradbury et al. studied 32 adults (mean age 39 years)
with OI type I who were treated with oral risedronate,
35 mg weekly, for 24 months; 27 completed the study.
Primary outcome measures were BMD changes at
lumbar spine (LS) and total hip (TH). Secondary out-
come measures were fracture incidence, bone pain and
change in bone turnover markers (serum procollagen
type I aminopropeptide (P1NP) and bone ALP). All
participants had multiple low-trauma fragility frac-
tures at an early age and blue sclerae, and most partici-
pants had a family history of OI type I. BMD increased
at LS by 3.9% (0.815 vs. 0.846 g/cm
2
,
p
= 0.007; mean
Z-score, −1.93 vs. −1.58,
p
= 0.002), with no significant
change at TH. P1NP fell by 37% (
p
= 0.00041), with no
significant change in bone ALP (
p
= 0.15). Bone pain did
not change significantly (
p
= 0.6). Fracture incidence
remained high, with 25 clinical fractures and 10 major
fractures in 14 participants (0.18 major fractures per
person per year), with historical data of 0.12 fractures
per person per year. The meta-analysis did not dem-
onstrate a significant difference in fracture incidence
in patients with OI treated with oral bisphosphonates.
During the 2-year study period, data were available for
27 participants. Twenty-five clinically apparent frac-
tures occurred in 14 participants. Ten major fractures
occurred in eight participants. The overall major frac-
ture incidence rate was 0.18 major fractures per person
per year. Three of five postmenopausal women partici-
pating in this study had a major fracture: two women
fractured a femur and one fractured her humerus
and a vertebra. Excluding postmenopausal women,
seven major fractures occurred in five of the remain-
ing 23 participants, giving an incidence rate of 0.15
major fractures per person per year. Two participants
who had not recalled any fractures in the preceding
5 years had a major fracture during follow-up. The
authors concluded that risedronate in adults with OI
type I results in modest but significant increases in
BMD at the lumbar spine and decreased bone turnover.
However, this did not make a clinically significant dif-
ference to fracture incidence.
44
In summary, in contrast to postmenopausal osteopo-
rosis, no study to date has demonstrated a significant
decrease in fracture rate in adults with OI treated with
bisphosphonates either orally or IV.
TERIPARATIDE TREATMENT
IN ADULT OI
Parathryroid hormone (PTH) increases osteoblast bone
formation.
45
In addition, PTH inhibits sclerostin expres-
sion by bone osteocytes thus stimulating bone forma-
tion.
46
Teriparatide (rh1-34 parathyroid hormone) is an
effective treatment for postmenopausal osteoporosis.
47
A randomized, double-blinded, placebo-controlled trial
of teriparatide, 20 µg daily, administered SQ daily for 18
months to patients with OI was recently completed by
Orwoll et al. (
Figure 55.3
).
48
Teriparatide therapy in adults
with OI resulted in: (1) changes in biochemical param-
eters of bone turnover similar to those observed in simi-
lar studies in patients with osteoporosis; (2) increases in
areal BMD at the hip and spine; (3) a substantial increase
in volumetric spine BMD and calculated finite element
analysis of spine strength and a decrease in spine load-to-
strength ratio; and (4) although the study was not specifi-
cally powered to assess fracture incidence, there was no
significant change in the incidence of fracture.
Clinical fractures were reported by 14 (36%) in the
placebo and 11 (29%) of the teriparatide-treated group
(
P
= 0.63). The teriparatide group had non-significantly
lower odds of fracture 0.73 (RR: 0.28-1.90).
Larger numbers of study patients are required to
confirm these results. The mode of action of teripara-
tide is to increase osteoblast bone formation. However,
because in OI it is the osteoblast, the source of type I
collagen synthesis, which is compromised, these results
suggest that the lack of a teriparatide effect on fracture
rate may reflect a limited response based on the altera-
tion in osteoblast collagen metabolism.
AGENTS UNDER STUDY WITH
POTENTIAL APPLICATION TO OI
(CIRCA DECEMBER 2012)
Anti-Sclerostin Antibodies
The Wnt signaling pathway is essential to the regu-
lation of osteoblast function. The SOST gene encodes
for sclerostin, a protein expressed by osteocytes that
