Copyright 2016 American Medical Association. All rights reserved.
Effect of Abaloparatide vs Placebo on New Vertebral
Fractures in Postmenopausal Women With Osteoporosis
A Randomized Clinical Trial
Paul D. Miller, MD; Gary Hattersley, PhD; Bente Juel Riis, MD; Gregory C. Williams, PhD; Edith Lau, MD; Luis Augusto Russo, MD, PhD;
Peter Alexandersen, MD; Cristiano A. F. Zerbini, MD; Ming-yi Hu, PhD; Alan G. Harris, MD; Lorraine A. Fitzpatrick, MD; Felicia Cosman, MD;
Claus Christiansen, MD; for the ACTIVE Study Investigators
IMPORTANCE
Additional therapies are needed for prevention of osteoporotic fractures.
Abaloparatide is a selective activator of the parathyroid hormone type 1 receptor.
OBJECTIVE To determine the efficacy and safety of abaloparatide, 80 μg, vs placebo for
prevention of new vertebral fracture in postmenopausal women at risk of osteoporotic fracture.
DESIGN, SETTING, AND PARTICIPANTS The Abaloparatide Comparator Trial In Vertebral
Endpoints (ACTIVE) was a phase 3, double-blind, RCT (March 2011-October 2014) at 28 sites in
10 countries. Postmenopausal women with bone mineral density (BMD) T score ⱕ−2.5 and
>−5.0 at the lumbar spine or femoral neck and radiological evidence ⱖ2 mild or ⱖ1 moderate
lumbar or thoracic vertebral fracture or history of low-trauma nonvertebral fracture within the
past 5 years were eligible. Postmenopausal women (>65 y) with fracture criteria and a T score
ⱕ−2.0 and >−5.0 or without fracture criteria and a T score ⱕ−3.0 and >−5.0 could enroll.
INTERVENTIONS Blinded, daily subcutaneous injections of placebo (n = 821); abaloparatide,
80 μg (n = 824); or open-label teriparatide, 20 μg (n = 818) for 18 months.
MAIN OUTCOMES AND MEASURES Primary end point was percentage of participants with new
vertebral fracture in the abaloparatide vs placebo groups. Sample size was set to detect a 4%
difference (57% risk reduction) between treatment groups. Secondary end points included
change in BMD at total hip, femoral neck, and lumbar spine in abaloparatide-treated vs
placebo participants and time to first incident nonvertebral fracture. Hypercalcemia was a
prespecified safety end point in abaloparatide-treated vs teriparatide participants.
RESULTS Among 2463 women (mean age, 69 years [range, 49-86]), 1901 completed the
study. New morphometric vertebral fractures occurred less frequently in the active treatment
groups vs placebo. The Kaplan-Meier estimated event rate for nonvertebral fracture was
lower with abaloparatide vs placebo. BMD increases were greater with abaloparatide than
placebo (all P < .001). Incidence of hypercalcemia was lower with abaloparatide (3.4%)
vs teriparatide (6.4%) (risk difference [RD], −2.96 [95% CI, −5.12 to −0.87]; P = .006).
Participants With Fracture, No. (%) Abaloparatide vs Placebo
Abaloparatide
(n = 824)
Placebo
(n = 821)
Teriparatide
(n = 818)
Risk Difference
(95% CI)
RR or HR
(95% CI)
P
Value
New vertebral
fracture
4 (0.6) 30 (4.2) 6 (0.8) −3.64
(−5.42 to −2.10)
RR, 0.14
(0.05 to 0.39)
<.001
Nonvertebral
fracture
18 (2.7) 33 (4.7) 24 (3.3) −2.01
(−4.02 to −0.00)
HR, 0.57
(0.32 to 1.00)
.049
CONCLUSIONS AND RELEVANCE Among postmenopausal women with osteoporosis, the use
of subcutaneous abaloparatide, compared with placebo, reduced the risk of new vertebral
and nonvertebral fractures over 18 months. Further research is needed to understand the
clinical importance of RD, the risks and benefits of abaloparatide treatment, and the efficacy
of abaloparatide vs other osteoporosis treatments.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01343004
JAMA. 2016;316(7):722-733. doi:10.1001/jama.2016.11136
Last corrected on January 24, 2017.
Editorial page 715
Supplemental content at
jama.com
CME Quiz at
jamanetworkcme.com
Author Affiliations: Colorado Center
for Bone Research, Lakewood
(Miller); Radius Health, Waltham,
Massachusetts (Hattersley, Williams,
Hu, Harris, Fitzpatrick); Nordic
Bioscience, Copenhagen, Denmark
(Riis, Christiansen); Center for Health
& Medical Research, Hong Kong,
People’s Republic of China (Lau);
Center for Clinical and Basic
Research, Rio de Janeiro, Brazil
(Russo); Center for Clinical and Basic
Research, Vejle, Denmark
(Alexandersen); Centro Paulista de
Investigação Clinica; São Paulo, Brazil
(Zerbini); Clinical Research Center,
Helen Hayes Hospital, West
Haverstraw, New York (Cosman).
Group Information: The ACTIVE
Study Investigators are listed at the
end of the article.
Corresponding Author: Paul D.
Miller, MD, Colorado Center for Bone
Research, PC, 3190 S Wadsworth
Blvd, Ste 250, Lakewood, CO 80227
(millerccbr@aol.com).
Research
JAMA | Original Investigation
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O
steoporosis is associated with substantial social, eco-
nomic, and public health burdens. Based on 2010 US
Census data, Wright et al
1
estimated the prevalence
of osteoporosis among women aged 50 to 69 years at 3.4 mil-
lion. Another 18.8 million US women in that age group were
estimated to have low bone mass at the femoral neck or lum-
bar spine. Additionally, Cawthon et al
2
have estimated that
the lifetime risk of osteoporotic fracture for a 60-year-old
woman is 44%. Fractures are associated with decreased qual-
ity of life,
3
including reduced independence,
4
and osteopo-
rotic fractures
5,6
are associated with increased morbidity and
mortality.
7
Experiencing a major osteoporotic fracture increases the
risk of subsequent fractures,
8,9
and risk is highest in the first
few years after the fracture.
10-12
Osteoanabolic therapy is of-
ten recommended for women at risk of future fracture, in-
cluding those with recent fracture or with multiple fractures,
13
but evidence of rapid fracture protection is lacking.
14
Abaloparatide is a peptide that selectively binds to the RG
conformation of the parathyroid hormone type 1 receptor.
15
As
a result of its mechanism of action, it was hypothesized that
abaloparatide would have a more pronounced anabolic ac-
tion on bone compared with teriparatide.
The primary objective of this study was to determine the
efficacy and adverse events of subcutaneous abaloparatide use
compared with placebo for prevention of new vertebral frac-
ture in postmenopausal women with osteoporosis.
Methods
Study Design
The Abaloparatide Comparator Trial In Vertebral Endpoints
(ACTIVE) was an international, randomized, placebo- and
active-controlled trial including postmenopausal women
with osteoporosis. Women were randomized 1:1:1 to receive
daily subcutaneous injections of abaloparatide, 80 μg, or
matching placebo,or teriparatide, 20 μg. Abaloparatide and
matching placebo were administered using a double-blind
format, while teriparatide, because it could be administered
only via its trademarked injection pen, was given open label.
The treatment period was 18 months.
Study Participants
Postmenopausal women aged 49 to 86 years were eligible if
they had bone mineral density (BMD) by dual energy x-ray ab-
sorptiometry T score of less than or equal to −2.5 and greater
than −5.0 at the lumbar spine or femoral neck together with
radiologic evidence of at least 2 mild vertebral fractures or at
least 1 moderate vertebral fracture
16
or history of a low-
trauma fracture of the forearm, humerus, sacrum, pelvis, hip,
femur, or tibia within the past 5 years. Women older than 65
years who met fracture criteria but had a T score of less than
or equal to −2.0 and greater than −5.0 were eligible. Women
older than 65 years were eligible without fracture criteria if
either BMD T score was less than or equal to −3.0 and greater
than −5.0. Eligibility required normal serum values for cal-
cium, intact parathyroid hormone, phosphorus, and alkaline
phosphatase and a 25-hydroxyvitamin D level of greater than
15 ng/mL (37.5 nmol/L [SI conversion, multiply by 2.496]).
Women were excluded if they had more than 4 mild, moder-
ate, or any severe vertebral fractures (consistent with defini-
tions described by Genant et al
16
), fewer than 2 evaluable
lumbar vertebrae, or if hip BMD was unevaluable. Partici-
pants were ineligible if they had evidence of metabolic bone
disease or malabsorption or were taking any medications that
would interfere with bone metabolism. Women were also
excluded if they used bisphosphonates for more than 3
months in the past 5 years or denosumab within the past
year. Women with a history of osteosarcoma were also
excluded. (See the ACTIVE Trial Protocol in Supplement 1 for
full inclusion and exclusion criteria.)
Participants provided written informed consent, and
the protocol was approved by the respective institutional
review boards.
Randomization and Blinding
Between April 26, 2011, and March 11, 2013, participants were
randomized using a permuted-blocks design with a block size
of 6 in a ratio of 1:1:1 to 1 of the 3 treatment groups. Random-
ized distribution of participants to study groups was double-
blind. Abaloparatide and placebo were administered with
identical pen injector devices under identical storage and dis-
pensing conditions. Because the teriparatide device is a
trademarked pen, it could not be reproduced, and the drug is
not approved for dispensing from a different injection device
(eg, a syringe) to blind it. After opening the identical assigned
study medication kit after randomization on day 1, it became
apparent to investigators and patients whether open-label
teriparatide or either double-blind abaloparatide or double-
blind placebo had been assigned.
Efficacy End Points
The primary efficacy end point of this study was the percent-
age of participants with 1 or more incidents of new morpho-
metric vertebral fracture. Anteroposterior and lateral radio-
graphs of the lumbar and thoracic spine were obtained
at baseline and at the end of treatment. Radiologists
(Bioclinica-Synarc) graded each woman’s vertebrae according
to the semiquantitative technique of Genant et al
16
which
Key Points
Question Is abaloparatide effective compared with placebo and
teriparatide when used as a treatment to reduce the risk of new
vertebral and nonvertebral fractures?
Findings This double-blind randomized clinical trial including
2463 postmenopausal women with osteoporosis showed that
abaloparatide was associated with significantly greater reduction
in incidence of new vertebral fractures and nonvertebral fractures
compared with placebo. Hypercalcemia was less frequent with
abaloparatide than with teriparatide.
Meaning Abaloparatide may represent a meaningful treatment
option for postmenopausal women who have osteoporosis but
requires testing against other osteoporosis treatments.
Abaloparatide vs Placebo for Vertebral Fracture Prevention in Osteoporotic Women Original Investigation Research
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defines a decrease in height of 20% to 25% as mild, 26% to
40% as moderate, and more than 40% as severe. Treatment
was blinded from radiologists. A second radiologist reviewed
radiographs in which an incident fracture had been identified
to confirm the reading; if necessary, a third radiologist adju-
dicated the incident fracture. All treatments were blinded
from adjudicators.
Nonvertebral fractures (a secondary end point) were frac-
tures that excluded those of the spine, sternum, patella, toes,
fingers, skull, and face and those with high trauma, defined as
a fall from a height equal to or higher than the level of a stool,
chair, or the first rung of a ladder. These nonvertebral fractures
were initially self-reported but required verification from source
documents. Treatments were blinded from all assessors.
Changes in BMD from baseline were assessed at total
hip, femoral neck, and lumbar spine at months 6, 12, and 18
(Bioclinica-Synarc). Serum markers of bone turnover, pro-
collagen type I N-terminal propeptide (s-PINP), and
carboxy-terminal cross-linking telopeptide of type I colla-
gen (s-CTX) were measured at months 1, 3, 6, 12, and 18
(Nordic Biosciences) in a subset of participants.
Per the study’s statistical analysis plan (Supplement 2), pre-
planned exploratory end points included assessment of clini-
cal fractures (all fractures that would cause a patient to seek
medical care, regardless of the level of trauma, including clini-
cal spine), major osteoporotic fractures (fractures of the up-
per arm, wrist, hip, or clinical spine), and analyses comparing
abaloparatide and teriparatide.
Safety
Safety evaluations included physical examinations, assess-
ment of vital signs, clinical laboratory tests, and reporting of
adverse events at each study visit. Twelve-lead electrocardio-
grams were performed at screening and at each study visit
prior to and 1 hour after injection of study drug. Serum cal-
cium concentrations were assessed at preinjection and at 4
hours postinjection on day 1, at months 1, 3, 6, 9, and 12, and
in the morning only at the month 18 visit. The protocol
allowed discontinuation of calcium, vitamin D, and the study
drug for hypercalcemia or hypercalciuria, which caused 1
participant from the abaloparatide group and 1 patient from
the teriparatide group to discontinue study participation.
The protocol specified that participants be withdrawn
from the study if they had confirmed significant deteriora-
tion from baseline (>7.0%) of BMD at lumbar spine or hip;
experienced treatment-related serious adverse events; devel-
oped severe hypersensitivity to subcutaneous abaloparatide
or teriparatide; were unable to complete study treatment;
refused treatment; developed protocol-defined hypercalce-
mia or hypercalciuria; or were lost to follow-up. Adverse
events and serious adverse events were coded according to
the Medical Dictionary for Regulatory Activities 17.1.
Study Oversight
This study was conducted in compliance with Good Clinical
Practice and the ethical principles stated in the Declaration of
Helsinki. Several measures were prespecified to assure par-
ticipant safety. Participants were not enrolled unless they com-
pleted an extensive informed consent evaluation. All partici-
pants were provided calcium and vitamin D and were required
to meet a minimal vitamin D level for enrollment. Partici-
pants with confirmed bone loss from baseline of greater than
7.0% at the lumbar spine, total hip, or femoral neck were dis-
continued from the study. Participants who experienced a frac-
ture while in the study were offered an option to discontinue
and receive alternative treatment. All participants in the sub-
cutaneous abaloparatide and placebo groups were offered, af-
ter 18 months of treatment, enrollment in an extension study
in which they were treated with alendronate for 24 months.
Study protocols were approved by appropriate health authori-
ties and ethics committees at each site. An independent data
and safety monitoring board monitored study safety (see eAp-
pendix 2 in Supplement 3 for a listing of members).
Statistical Analysis
A statistical analysis plan (available in Supplement 2) was
created prior to data finalization and unblinding. There were
3 populations for efficacy analyses. The intent-to-treat (ITT)
population, which included all participants who were ran-
domized into the study and received a study medication kit
on day 1, was the primary population used for all efficacy
analyses except for those of vertebral fracture. The modified
ITT population, which included all ITT participants who had
both pretreatment and postbaseline spine x-rays, was the pri-
mary population used for analyses of vertebral fracture only.
The per-protocol population, which included modified ITT
participants who adhered with treatment and had no proto-
col violations, was used as a supportive population for effi-
cacy analyses; findings for the per-protocol population,
which were consistent with the ITT analyses, are not
included in this report.
The primary efficacy end point of this study was the per-
centage of participants with 1 or more incidents of new mor-
phometric vertebral fracture comparing abaloparatide and
placebo. Key secondary end points included percent change
in BMD at the total hip, femoral neck, and lumbar spine at 18
months and incident nonvertebral fractures, both of which
were compared between abaloparatide and placebo. Addi-
tional comparisons are also described in this section. To con-
trol the overall significance level, a sequential testing plan
(with 8 specific tests after the primary comparison) was
defined. A hierarchical approach
17
controlled the overall type
I error rate at the 2-sided significance level of 5% by prespeci-
fying the order of the hypothesis tests in a fixed sequence
before performing the tests. The efficacy end points were
tested in the following sequence: new vertebral fracture (aba-
loparatide vs placebo); BMD at the total hip, femoral neck,
lumbar spine (abaloparatide vs placebo at 18 months); non-
vertebral fracture (abaloparatide vs placebo); BMD at the
total hip and femoral neck (abaloparatide vs teriparatide at 6
months); nonvertebral fracture (abaloparatide vs teripara-
tide); and BMD at lumbar spine (abaloparatide vs teriparatide
at 6 months). Each of the tests was performed sequentially at
the 2-sided significance level of 5% to claim statistical signifi-
cance. At any step, if the significance level of 5% was not
attained, the P values for the subsequent comparisons were
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generated as nominal for exploratory purposes. All statistical
analyses other than the fixed sequential testing were pre-
specified exploratory analyses, including analyses of clinical
fractures and major osteoporotic fractures, which are
described in this report.
The number of women with at least 1 new vertebral frac-
ture was compared using the Fisher exact test (between aba-
loparatide and placebo groups in the modified ITT popula-
tion). To evaluate the statistical effect of missing data on
incidence of new vertebral fractures, a sensitivity analysis was
performed based on the multiple imputation method. This
method used a logistic regression model to augment the data
set by imputing the missing outcome multiple times to char-
acterize the uncertainty of the imputation. The covariates in
the logistic model are listed in the statistical analysis plan
(Supplement 2). The primary efficacy analysis was repeated
using each of the augmented data sets, and the results were
combined according to Rubin.
18
Results of the sensitivity analy-
sis were similar to the primary efficacy analysis.
Time to nonvertebral fracture was compared using the log-
rank test in all participants through the whole observational
period of 19 months (18 months of treatment plus 1 month of
follow-up). The Cox proportional hazards model was used to
calculate hazard ratios (HRs). Formal statistical tests were per-
formed in abaloparatide vs placebo groups and abaloparatide
vs teriparatide groups as specified in the sequential testing plan.
This study reports percent change in BMD from baseline
at each study visit, which was compared using a mixed-effect
repeated-measure model. An analysis of covariance model with
missing data imputed and based on the last observation car-
ried forward is reported in eFigure 1 (in Supplement 3).
Bone turnover marker levels, reported as a log ratio of post-
baseline divided by baseline, were compared among groups
using a mixed-effect repeated-measure model on a randomly
selected subset of approximately 200 participants in each treat-
ment group with paired measurements at baseline and follow-
up. Treatment differences in log values were transformed into
geometric mean ratios for treatment comparisons (eFigure 2
in Supplement 3). Median percent change from baseline in bone
turnover marker levels was graphically displayed among treat-
ment groups. Hypercalcemia, defined as albumin-corrected se-
rum calcium of at least 10.7 mg/dL (≥2.67 mmol/L) at any time
point, was a prespecified safety end point and was analyzed
using a χ
2
test.
The sample size was determined to provide 90% power at
a 2-sided α of .05 to detect a difference of 4% between treat-
ments, assuming a vertebral fracture rate of 7% in partici-
pants receiving placebo and 3% in participants receiving aba-
loparatide, a difference of 4%, equivalent to 57% risk reduction.
The sample size was calculated using a large-scale binomial
approximation. The required sample size was 622 per group.
To ensure an analysis size of 622 women, an overall sample
size of approximately 800 per treatment group was re-
cruited, anticipating that approximately 20% of participants
might not have a second set of evaluable radiographs avail-
able for analysis. This sample size would provide more than
90% power to detect significant percentage changes, consis-
tent with other drugs, in total hip, femoral neck, and lumbar
spine BMD. It would provide similar power to detect differ-
ences in hypercalcemia incidence between the abaloparatide
and teriparatide groups.
All statistical analyses were performed using SAS version 9.4.
Results
A total of 5268 women underwent screening for the trial. There
were 2032 who failed to meet eligibility criteria, 698 declined
participation, 53 were not randomized, and 22 were excluded
for other reasons (Figure 1).
A total of 2463 women were randomized at 28 study cen-
ters in 10 countries to receive abaloparatide (n = 824 [33.5%]),
placebo (n = 821 [33.3%]), or open-label teriparatide (n = 818
[33.2%]). Overall, 1901 participants (77.2%) completed all study
visits: 637 (77.6%) in the placebo group, 606 (73.5%) in the aba-
loparatide group, and 658 (80.4%) in the teriparatide group,
and 2118 (86%) participants had postrandomization radio-
graphs that were assessed for new morphometric vertebral frac-
tures (primary end point).
At baseline, mean age was 68.8 years, and mean femoral
neck T score was −2.1. Approximately 24% of participants had
a prevalent vertebral fracture, 31% reported a history of non-
vertebral fracture within the past 5 years, and 37% had no prior
fractures (Table 1). Baseline characteristics were similar among
treatment groups. During the study, the mean daily dosages
of vitamin D were 613 IU in the placebo group, 723 IU in the
abaloparatide group, and 625 IU in the teriparatide group, and
mean daily calcium dosages were 986 mg in the placebo group,
955 mg in the abaloparatide group, and 894 mg in the teripa-
ratide group.
Each participant recorded study drug administration and
local tolerance in a weekly diary. According to the duration of
each individual’s exposure during this study treatment pe-
riod (when participants were to remain on study medica-
tion), mean percent adherence to study drug administration
was greater than 90% for each of the 3 treatment groups.
Primary Outcome
New morphometric vertebral fractures occurred in 0.58%
(n = 4) of participants in the abaloparatide group and in 4.22%
(n = 30) of those in the placebo group (risk difference [RD] vs
placebo, −3.64 [95% CI, −5.42 to −2.10]; relative risk, 0.14 [95%
CI, 0.05 to 0.39]; P < .001; Table 2). In the teriparatide group,
new morphometric vertebral fractures occurred in 0.84%
(n = 6) of participants (RD vs placebo, −3.38 [95% CI, −5.18 to
−1.80]; relative risk, 0.20 [95% CI, 0.08 to 0.47]; P < .001). Re-
sults of the sensitivity analysis were similar to results of the
primary efficacy analysis.
Secondary Outcomes
Secondary outcomes for this study are reported in hierarchi-
cal order as defined by the statistical analysis plan (in
Supplement 2). Compared with placebo at 18 months, the
abaloparatide-treated group demonstrated significant changes
from baseline BMD at the total hip (4.18% vs −0.10%; treat-
ment difference, 4.25% [95% CI, 3.90% to 4.59%]), femoral
Abaloparatide vs Placebo for Vertebral Fracture Prevention in Osteoporotic Women Original Investigation Research
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Figure 1. Patient Flow Through Phases of a Randomized Trial of Abaloparatide vs Placebo for New Vertebral Fracture Prevention
Among Postmenopausal Women With Osteoporosis
5268 Patients screened
2805 Excluded
2032 Did not meet eligibility requirements
695 Did not meet study x-ray inclusion criteria
687 Did not meet study laboratory parameter
inclusion criteria
650 Did not meet clinical inclusion criteria
698 Declined participation
53 Not randomized
50 Randomization had been stopped
2 Serious adverse event
a
1 Missing
22 Other reasons
2463 Randomized
818 Randomized to receive teriparatide
818 Received teriparatide
as randomized
821 Randomized to receive placebo
820 Received placebo as randomized
1 Did not receive placebo
as randomized (refused
treatment)
824 Randomized to receive
subcutaneous abaloparatide
822 Received abaloparatide
as randomized
2 Did not receive abaloparatide
as randomized (withdrew consent)
717 Included in the primary outcome
analysis (new vertebral fracture)
101 Did not have postbaseline
radiologic assessment and were
not analyzed for new vertebral
fracture
818 Included in nonvertebral fracture
analysis
818 Included in safety analysis
711 Included in the primary outcome
analysis (new vertebral fracture)
110 Not included in primary outcome
analysis
821 Included in nonvertebral fracture
analysis
820 Included in safety analysis
109 Did not have postbaseline
radiologic assessment
1 Did not have pretreatment
radiologic assessment
690 Included in the primary outcome
analysis (new vertebral fracture)
134 Did not have postbaseline
radiologic assessment and were
not analyzed for new vertebral
fracture
824 Included in nonvertebral fracture
analysis
822 Included in safety analysis
658 Completed the study
3 For ≤18 months
426 For >18 months to 19 months
229 For >19 months
637 Completed the study
1 For ≤18 months
386 For >18 months to 19 months
250 For >19 months
606 Completed the study
0 For ≤18 months
320 For >18 months to 19 months
286 For >19 months
184 Lost to follow-up
89 ≤6 Months
48 >6 Months to ≤12 months
47 >12 Months to <18 months
Reasons for loss to follow-up
53 Adverse event
48 Withdrew consent
33 Refused treatment
14 Nonadherence or protocol violation
12 Decrease in bone mass density
at spine or hip (>7% bone loss)
7 Inability to complete study procedures
5 Died
1 Severe sensitivity to
abaloparatide or placebo
11 Other
b
218 Lost to follow-up
131 ≤6 Months
47 >6 Months to ≤12 months
40 >12 Months to <18 months
Reasons for loss to follow-up
89 Adverse event
47 Withdrew consent
31 Refused treatment
11 Inability to complete study procedures
10 Nonadherence or protocol violation
4 Serious intercurrent illness
3 Died
1 Protocol-defined hypercalcemia
or hypercalciuria
1 Decrease in bone mass density
at spine or hip (>7% bone loss )
21 Other
b
160 Lost to follow-up
82 ≤6 Months
43 >6 Months to ≤12 months
35 >12 Months to <18 months
Reasons for loss to follow-up
53 Adverse event
45 Withdrew consent
19 Refused treatment
14 Nonadherence or protocol violation
5 Serious intercurrent illness
5 Inability to complete study procedures
2 Died
1 Protocol-defined hypercalcemia
or hypercalciuria
1 Decrease in bone mass density
at spine or hip (>7% bone loss)
2 Treatment-related serious
adverse event
13 Other
b
a
Two women experienced events that resulted in hospitalization and were
therefore categorized as having serious adverse events (1, fracture of the left
femoral neck; 1, head of the humerus fracture); however, these events
occurred prior to and, in fact, prevented randomization. They were not
associated with study treatment.
b
Category includes patients lost to follow-up for the following reasons: did not
return, refused to perform procedures, no longer wished to participate,
administrative reasons, unknown reasons, and breast cancer (1 patient).
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