Use of Depot Medroxyprogesterone

Acetate Contraception and Incidence

of Bone Fracture
Lee L. Lanza, ScD, Lisa J. McQuay, MBioinf, Kenneth J. Rothman, DrPH, Henry G. Bone, MD,
Andrew M. Kaunitz, MD, Zeev Harel, MD, Quazi Ataher, PhD, Douglas Ross, MD, Philip L. Arena, BSPharm,
and Kevin D. Wolter, MD
OBJECTIVE: Depot medroxyprogesterone acetate (DMPA)
reversibly reduces bone mineral density. To estimate the
extent to which DMPA might increase fracture risk, we
undertook a retrospective cohort study of fractures in
DMPA users and users of non-DMPA contraceptives, using
the General Practice Research Database.
METHODS: Eligible women were aged younger than 50
years at the qualifying first contraceptive prescription.
The DMPA users were classified by DMPA exposure
(cumulative and time of last dose) based on prescription
records. All incident fractures were included; fracture
incidence and risk factors before starting contraceptive
use (DMPA or other) also were estimated.
From RTI Health Solutions, Waltham, Massachusetts, and Research Triangle
Park, North Carolina; the Michigan Bone & Mineral Clinic, Detroit, Michigan;
the Department of Obstetrics and Gynecology, University of Florida College of
Medicine-Jacksonville, Jacksonville, Florida; the Division of Adolescent Medicine/
Hasbro Childrens Hospital and the Department of Pediatrics/Warren Alpert
Medical School, Brown University, Providence, Rhode Island; and Pfizer, Collegeville, Pennsylvania, and New York, New York.
Supported by Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ,
United Kingdom. The sponsor (Pfizer) funded the study, contributed to the design
of the study, the interpretation of the results, and the writing of the report, and
provided funding for editorial support (formatting and editing of the final draft),
but did not have access to the raw data. Editorial support (formatting and editing
of the final draft) was provided by Julie Ponting of Anthemis Consulting Ltd and
Abegale Templar, PhD, of UBC Scientific Solutions.
Presented at the Reproductive Health 2010 Annual Meeting of the Association of
Reproductive Health Professionals, September 2225, 2010, Atlanta, Georgia.
Corresponding author: Dr. Lee Lanza, RTI Health Solutions, 1440 Main Street,
Suite 310, Waltham, MA 02451; e-mail: llanza@rti.org (www.rti-hs.org).
Financial Disclosure
Lee L. Lanza, Lisa J. McQuay, and Kenneth J. Rothman are employees of RTI
Health Solutions, which was under contract to Pfizer for the work leading to this
article. Henry Bone has received research grant support and consulting fees from
Pfizer. Zeev Harel has received research grant support from Pfizer. Quazi Ataher,
Douglas Ross, Philip L. Arena, and Kevin D. Wolter are employees of Pfizer.
Andrew Kaunitz reports no conflicts of interest.
2013 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/13

VOL. 121, NO. 3, MARCH 2013

RESULTS: We identified 11,822 fractures in 312,395

women during 1,722,356 person-years of follow-up.
Before contraceptive use started, DMPA users had higher
fracture risk than nonusers (incidence rate ratio 1.28,
95% confidence interval [CI] 1.071.53). After DMPA
started, crude fracture incidence was 9.1 per 1,000
person-years for DMPA users and 7.3 for nonusers
(crude incidence rate ratio 1.23, 95% CI 1.161.30). Fracture risk in DMPA users did not increase after starting
DMPA (incidence rate ratio after or before 1.08, 95% CI
0.921.26). There was little confounding by age or other
factors that could be measured. Fracture incidence was
9.4 per 1,000 person-years in low-exposure DMPA users,
and 7.8 per 1,000 in high-exposure DMPA users. The
DMPA users had higher fracture risk than nonusers at
the start of contraceptive use, with no discernible induction period.
CONCLUSION: Although DMPA users experienced
more fractures than nonusers, this association may be
the result of confounding by a pre-existing higher risk for
fractures in women who chose DMPA for contraception.
(Obstet Gynecol 2013;121:593600)
DOI: http://10.1097/AOG.0b013e318283d1a1

LEVEL OF EVIDENCE: II

epot medroxyprogesterone acetate (DMPA; 150

mg intramuscular or 104 mg subcutaneous injection), a long-acting reversible contraceptive used
globally by women who require high contraceptive
efficacy without increased thromboembolic risk,1,2
decreases bone mineral density (BMD)3,4 in adults in
a reversible manner,5,6 with mean BMD declines of
5.4% (lumbar spine) and 5.2% (hip) after 5 years.7 In
adolescents, mean decreases of 2.7% (spine), 4.1%
(hip), and 3.9% (femoral neck) were reported, with spine
BMD returning to pre-exposure levels 60 weeks after
discontinuation.8 No evidence of reduced BMD was

OBSTETRICS & GYNECOLOGY

593

seen in postmenopausal women who had used DMPA

during their reproductive years.9
In postmenopausal women, low BMD is associated
with increased risk for fragility fractures (fractures
occurring with little or no trauma attributable to severely
compromised bone microarchitecture).10 Despite no
established relationship between low BMD and fragility fractures in premenopausal women, concern that
fracture risk could increase has led to limitations on
DMPA use.11 Literature searches were completed
using PubMed and Google Scholar for the years
19602012 using the search terms Depo-Provera,
Injectable medroxyprogesterone acetate, injectable
MPA, injectable contraceptive, MP IM (IM
MPA), DMPA or Depot MPA and fracture (fractures), fracture risk, osteoporosis, osteoporotic
fracture, fragility fracture, or bone fracture. No
study estimating fracture risk before and after DMPA
use has determined whether DMPA increases fracture
risk. The present retrospective cohort study was conducted to address two questions: what is the association between DMPA use and fracture incidence? and
does the association with fracture vary by level of
DMPA exposure?

MATERIALS AND METHODS

Using data in the General Practice Research Database,
this nonrandomized study compared fracture incidence
in two cohorts of women, DMPA users and women
using non-DMPA prescription contraceptives. The study
used anonymized data and was deemed by the Research
Triangle Institute Committee for the Protection of
Human Subjects to be exempt, under United States
law, from review by an Institutional Review Board.
The General Practice Research Database contains
de-identified longitudinal patient records from more
than 350 general practices in the United Kingdom
(www.gprd.com) and has been validated for drug safety
studies.1214 The General Practice Research Database
staff supplied electronic data for all women who met
the following study criteria: acceptable patient status by
General Practice Research Database data quality criteria; known year of birth; and at least one prescription
contraceptive record, including DMPA, oral contraceptives, intrauterine device (IUD), cervical cap, or
diaphragm, before age 50 years and before any record
of bilateral oophorectomy dated between 1 January
1987 and 31 December 2005. For each eligible patient,
we received all available General Practice Research
Database records before and after the first recorded
contraceptive prescription. These women constituted
the full study cohort. For investigation of confounding,
we restricted analysis to the subcohort of women who

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DMPA and Bone Fracture

had at least 6 months of baseline data before contraceptive use.

For each patient, the index date was defined as the
date of her first contraceptive prescription on or after
the latest of 1 January 1987, the womans practice registration date, or the date the practice was certified as
having met General Practice Research Database data
quality standards. Follow-up for each woman began on
the index date and continued until the first of the practices last contribution to General Practice Research
Database, 31 December 2005, the womans first
recorded fracture, or her termination from the practice.
Women who switched to DMPA after the index date
first contributed observation time to the nonuser group
(index date to first use of DMPA) and then to the
DMPA user group; women who began DMPA at the
index date contributed time only to the DMPA user
group, regardless of other contraceptive usage.
Baseline medical history was used to assess the
potential for possible confounding based on changes
in incidence rate ratio estimates for DMPA exposure
and fracture, with and without control of each
potential confounder. We used standardization for
the purpose of controlling confounding, based on
distribution weights of person-years in the subcohort
with at least 6 months of baseline history.
Each DMPA prescription generated 90 days of
exposure, based on prescribing information.11 Periods
of active exposure were defined by concatenating contiguous or overlapping prescription periods. Isolated
DMPA episodes occurred when 90-day exposure periods did not overlap or flank the exposure period for
another DMPA injection. Duplicate prescriptions
(same date) were deleted and records occurring fewer
than 63 days (fifth percentile for injection interval)
after the last DMPA injection were disregarded.
A womans period of active DMPA exposure
extended from her first injection within an episode to
the end of the 90-day exposure period of the last injection in the episode. Cumulative DMPA exposure
for each woman was categorized as low (one to seven
injections) or high (at least eight injections). We used
three categories of DMPA follow-up time: current
exposure was day 1 (DMPA administered) to day 90
(extended by 90 days for each new injection); recent
exposure extended until 730 days after the last injection, based on an assumed BMD recovery time of 2
years (range 1 5 years, depending on bone site)5,6;
and past exposure was all time 731 or more days after
the last injection, unless there was a new prescription
for DMPA.
We also examined fracture incidence over time in
DMPA users by calculating time-specific incidence

OBSTETRICS & GYNECOLOGY

rates since start of use. A Savitzky-Golay cubic polynomial smoothing filter with a 25-point window15 was
used to fit a trend line. To examine fracture rates
according to anatomic site, fracture events were coded
using the Read and Oxford Medical Information System dictionary. Multiple fractures on the same date
were counted as one event for incidence of any fracture. SAS 9 was used for basic analyses and Episheet
(http://krothman.hostbyet2.com/Episheet.xls) was
applied for standardizing rates and calculating confidence interval (CI) estimates of the standardized rates.
For incidence rate ratios of zero, we used Stata software 9 to estimate the upper bound of a 95% exact CI.
We analyzed fracture incidence before and after
the start of contraceptive use for women who used
DMPA at some point and performed a similar analysis for nonusers of DMPA with respect to use of their
qualifying non-DMPA contraceptive. This approach
controlled for unmeasured variables that may differ
between women but are generally constant over time
within a woman, such as behavioral or lifestyle
variables that are unavailable in the General Practice
Research Database and therefore cannot be directly
assessed but that could potentially affect the observed
incidence of fractures.
We divided the subcohort of women who had 6
or more months of baseline history into ever-users
and nonusers of DMPA, based on the choice of
contraceptive after the index date, and calculated time
to first fracture during the 6-month baseline period.
Observation time within the baseline period was less
than 6 months in those women who reported a fracture
during the baseline period, and exactly 6 months
otherwise. The number of person-years after starting
contraceptive use was calculated beginning with the
index date for nonusers or, for DMPA users, beginning with the date of first DMPA use and ending with
study termination. If a DMPA user did not start
DMPA on the study index date, the person-years of
nonuse that occurred between the study index date
and the start of DMPA use were not included in any
before calculations or after calculations. Fractures
during the baseline period were counted as any or
none. Individual fractures were identified by the
corresponding Read and Oxford Medical Information
System code and were grouped into categories (axial,
appendicular, or miscellaneous fractures) that may
correlate with fracture etiology.10

RESULTS
The General Practice Research Database provided
data for 330,684 women aged 1550 years at the
index date; 18,289 (5.5%) did not meet the eligibility

VOL. 121, NO. 3, MARCH 2013

criteria. The full study cohort included 312,395

women, and the subcohort with at least 6 months of
baseline history included 166,637 (53%) women. In
the full cohort, average follow-up was 5.9 years for
DMPA users and 5.4 years for nonusers. The most
common reason that follow-up terminated was reaching the 31 December 2005 end-of-study date (58.2%);
other reasons were that the woman stopped contributing data to the practice, including by transfer or
death (34.7%), an incident fracture (3.8%), or the practice stopped contributing data to General Practice
Research Database (3.4%).
In the full cohort, 11,822 fractures occurred
during 1,722,356 person-years of follow-up. Crude
fracture incidence at any skeletal site during follow-up
was 6.4 per 1,000 person-years for nonusers (8,887
fractures in 1,395,041 person-years) and 9.0 per 1,000
person-years for DMPA users (2,935 fractures in
327,315 person-years); the crude incidence rate ratio
after contraception started was 1.41 (95% CI 1.35
1.47). Table 1 shows age-specific fracture rates in the
full cohort.
In addition to the crude overall rates, fracture rate
also was analyzed after being compared with results
before DMPA or other contraception was initiated in
the subgroup of participants with fracture data available before the index date; according to DMPA
exposure (less than eight injections compared with
eight or more injections) in the full cohort of DMPA
users, and according to the anatomic location of the
fracture in the full cohort of all participants. These
analyses were performed after the magnitude of
confounding had been assessed. Therefore, we present both the crude results and results standardized for
measured confounders, as described.
To examine the potential for confounding of the
results by pre-existing characteristics of the women in
the study, the relevant demographic and medical
history variables for which records were available in
the General Practice Research Database were individually assessed as potential confounders.
In the subcohort of women who had at least 6
months of baseline history available in the General
Practice Research Database (n5166,367), fracture
incidence after contraception started was similar to
that in the full cohort. The crude fracture incidence
rate was 6.6 per 1,000 person-years for nonuse of
DMPA (4,939 cases in 744,242 person-years) and
9.1 per 1,000 person-years during DMPA use (1,574
cases in 173,713 person-years). The crude incidence
rate ratio for any fracture in the subcohort was 1.37
(95% CI 1.291.45) and the crude incidence rate difference was 2.42 per 1,000 person-years (95% CI

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595

Table 1. Age-Specific Incidence Rates of Fracture Per 1,000 Person-Years by Ever-Use of Depot
Medroxyprogesterone Acetate in the Full Cohort of 312,395 Women
DMPA User (n579,065)
Age (y)

DMPA Nonuser (n5233,330)

No. of Fractures

Person-Years

Rate

No. of Fractures

Person-Years

Rate

5
248
588
621
611
417
287
115
34
8
1
2,935

485
28,278
65,014
72,140
67,929
51,990
27,933
10,696
2,480
339
31
327,315

10.3
8.8
9.0
8.6
9.0
8.0
10.3
10.8
13.7
23.6
32.6
9.0

38
971
1,421
1,569
1,631
1,371
934
587
276
77
12
8,887

5,591
129,985
222,942
270,691
280,389
225,285
144,628
78,589
29,249
7,050
642
1,395,041

6.8
7.5
6.4
5.8
5.8
6.1
6.5
7.5
9.4
10.9
18.7
6.4

Younger than 15
1519
2024
2529
3034
3539
4044
4549
5054*
5559*
6065*
Total

DMPA, depot medroxyprogesterone acetate.

* Women were aged 50 years or younger at index date but were followed-up past age 50 years, and some fractures occurred after age 50
years.

1.942.91 per 1,000 person-years). In this subcohort,

the age-standardized fracture rate per 1,000 personyears was 6.6 for nonusers and 9.3 for DMPA users,
giving a standardized incidence rate ratio of 1.40
(95% CI 1.321.49) and a standardized incidence rate
difference of 2.6 per 1,000 person-years (95% CI
2.133.17 per 1,000 person-years). These results are
close to the crude results, indicating little confounding
by age within the age range of the study population.
Table 2 shows the crude associations for each
baseline variable with DMPA use and fracture risk,
along with the incidence rate ratio standardized for

age and potential confounders. All results were very

close to the incidence rate ratio obtained when controlling only for age, indicating that none of the other
potential confounders for which data were available in
the General Practice Research Database contributed
any material confounding to the overall incidence rate
ratio for DMPA and fractures.
For the analyses of fracture incidence according
to DMPA exposure and fracture site, the lack of
confounding by measured risk factors for fracture
prompted us to expand the study population to the
full cohort of 312,395 women, including the 146,028

Table 2. Summary of Identified Potential Confounders in the Subcohort of 166,367 Women With Baseline
History
Proportion of Person-Years
in Exposure Categories
Potential Confounders
Total person-years
Past fracture, any site
Alcohol abuse or dependence
Drug abuse
Inflammatory bowel disease
Epilepsy
Asthma
Oral corticosteroid therapy
Baseline fall
Estrogen replacement therapy
Smoking, current
Pregnancy, age younger than 20 y

DMPA User

DMPA Nonuser

Incident Rate Ratio

for Fracture by
Presence of Risk
Factor (Yes or No)

173,713
0.0039
0.0014
0.0012
0.0010
0.0020
0.0212
0.0098
0.0043
0.0022
0.1851
0.1103

744,242
0.0029
0.0007
0.0004
0.0007
0.0010
0.0153
0.0074
0.0024
0.0059
0.1092
0.0755

4.9
3.8
2.9
2.1
2.0
1.6
1.4
1.4
1.4
1.3
1.2

Incident Rate
Ratio (95% CI) for
Fracture, Adjusted for
Age and Risk Factor*
1.41
1.41
1.40
1.40
1.40
1.39
1.40
1.40
1.40
1.39
1.40

(1.321.50)
(1.321.49)
(1.321.48)
(1.321.48)
(1.321.48)
(1.311.48)
(1.321.49)
(1.321.49)
(1.321.49)
(1.311.47)
(1.321.49)

CI, confidence interval; DMPA, depot medroxyprogesterone acetate.

* DMPA use during the study period, compared with nonuse of DMPA.

Incident rate ratios are standardized for age in 5-year groups and for each factor (one at a time).

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OBSTETRICS & GYNECOLOGY

who had less than 6 months of medical history

available before their index date, on the assumption
that confounding as defined similarly would not be
material for these additional women.
Table 3 shows that before contraception was
started, the crude incidence rate ratio for fractures
for women who later became DMPA users was 1.28
(95% CI 1.071.53) compared with women who never
used DMPA. Further, neither of these two cohorts
exhibited a meaningful increase in fracture rate after
starting contraception. The incidence rate ratio for
fracture in DMPA users (after and before) was 1.08
(95% CI 0.921.26). In these analyses, 72,190 personyears of nonuse by DMPA users who started DMPA
after the index date were excluded.
Fracture history during the 6-month baseline
period immediately preceding first contraceptive use
was not identified as an important confounder in the
age-standardized analyses because the follow-up data
from the 585 women with a baseline fracture history
did not materially influence the overall results. That is,
the overall incidence rate ratio for fracture was similar
with and without these relatively few women included
in the analysis (Table 2). Nonetheless, both before and
after contraception started, DMPA users had a greater
fracture incidence than nonusers (Table 3).
Table 4 shows the effects of DMPA exposure by
recency of use and cumulative number of injections.
For current DMPA users compared with nonusers,
crude excess fracture risk was greater in low-exposure
users (incidence rate ratio 1.91, 95% CI 1.762.06) than
in high-exposure users (incidence rate ratio 1.09, 95% CI
0.981.21) whose fracture risk was not different from that
of nonusers. Age-standardized rates gave similar results.
For recent and past DMPA use, fracture risk was similar
between low-exposure and high-exposure users.
Figure 1 shows fracture incidence at each time point
(1/10th year) since starting DMPA for current and recent

users of DMPA, with a reference line indicating the nonuser incidence rate. The data points are statistically stable
through approximately 1,500 days but are based on few
events per time point after 1,500 days. Overall, the graph
indicates that current and recent users do have a higher
fracture rate than nonusers, but it is noteworthy that
there was no important time trend with continuing use.
In particular, the difference in risk between DMPA users
and nonusers was present at the start of use, showed no
discernible induction period during which BMD could
have declined before fracture incidence increased in
DMPA users, and did not meaningfully change up to
day 1,500. The graph excludes periods of use for
a woman that occurred after a gap of more than 2 years
since her previous period of use.
Compared with nonuse, DMPA users had more
codes for appendicular and miscellaneous (fingers,
toes, face, skull, multiple trauma, and unspecified)
fractures (Table 5); however, there was no excess risk
for axial fracture codes (hip, pelvis, and symptomatic
or clinical vertebral fractures; incidence rate ratio
0.95, 95% CI 0.741.23).

DISCUSSION
When used consistently and correctly, DMPA has
contraceptive efficacy (0.22 failures per 100 personyears) comparable to IUDs and implants (0.27 failures);1 nevertheless, the possibility of an adverse effect
on fractures has been a long-standing concern. However, the results of this study suggest that DMPA does
not increase risk for fracture.
Hypoestrogenemia lowers BMD and, as a consequence, fracture risk is increased in postmenopausal
women whose bone structures have been compromised because of large BMD declines (more than
20%) early in menopause;16,17 however, no similar
BMDfracture relationship has been demonstrated
for reproductive-aged women. Therefore, as Grimes

Table 3. Incidence Rate and Crude Rate Ratio for Fracture by Ever-Use of Depot Medroxyprogesterone
Acetate and by Observation Period in the Subcohort of 166,367 Women With Baseline History
Before Starting Contraceptive
No. With
Fracture
DMPA users (n541,876)
DMPA never-users (n5124,491)
Crude incident rate ratio for DMPA
compared with nonuse (95% CI)

176
409
1.28 (1.071.53)

Rate/1,000
Person-Years*
8.4
6.6

After Starting Contraceptive

After or Before

No. With
Fracture

Rate/1,000
Person-Years*

Incident Rate
Ratio (95% CI)

9.1
7.3

1.08 (0.921.26)
1.12 (1.011.24)

1,574
4,939
1.23 (1.161.30)

DMPA, depot medroxyprogesterone acetate; CI, confidence interval.

* Before starting contraceptive, person-years were 20,933 (DMPA) and 62,268 (nonuser); after starting contraceptive, person-years were
173,713 (DMPA) and 672,052 (nonuser, excluding 72,190 person-years of nonuse contributed by DMPA ever-users who used a nonDMPA contraceptive starting at the index date, before their first DMPA injection).

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Table 4. Crude Incidence of Any Fracture by Cumulative Number of Depot Medroxyprogesterone Acetate
Injections and Time From Last Depot Medroxyprogesterone Acetate Injection in the Full Cohort
Exposure
Nonusers
All DMPA
Low
High
All past DMPA
Low
High
All recent DMPA
Low
High
All current DMPA
Low
High

Fractures

Person-Years

Fractures Per 1,000

Person-Years*

8,887
2,935
2,288
647
1,011
892
119
931
751
180
993
645
348

1,395,041
327,315
244,278
83,037
119,928
106,400
13,528
103,984
84,755
19,228
103,404
53,123
50,281

6.4
9.0
9.4
7.8
8.4
8.4
8.8
9.0
8.9
9.4
9.6
12.1
6.9

Incident Rate
Ratio (95% CI)
1.41
1.47
1.22
1.32
1.32
1.38
1.41
1.39
1.47
1.51
1.91
1.09

1.00
(1.351.47)
(1.401.54)
(1.131.32)
(1.241.41)
(1.231.41)
(1.151.65)
(1.311.50)
(1.291.50)
(1.271.70)
(1.411.61)
(1.762.06)
(0.981.21)

CI, confidence interval; DMPA, depot medroxyprogesterone acetate.

* Age-standardized rates (not shown) are not different from the crude rates.

Nonexposure includes person-years of never-users and person-years of DMPA users before first DMPA prescription. Current exposure
time indicates active DMPA use based on the interleaving of active 90-day exposures generated by each injection; recent exposure is
640 or fewer days after the last active exposure; and past exposure begins after recent exposure.

Low exposure: one to seven DMPA injections.

High exposure: eight or more injections.

and Schulz18 have suggested, BMD may be an inappropriate surrogate endpoint in this population.
Previous database studies of DMPA and fracture
applied different types of cohorts and age ranges,
making comparison with the current studys cohort of
contraceptive users potentially difficult; however, the

Fig. 1. Crude incidence of fracture during current recent

exposure time after first depot medroxyprogesterone acetate (DMPA) injection. Circles represent unsmoothed data
points for the fracture rates in DMPA users per interval of
the life-table (1/10th year). Each data point up to day 1,516
contains at least 10 incident fractures. The figure was
truncated when most intervals had zero to two incident
fractures.
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age-specific and gender-specific fracture rates reported by Van Staa et al16 for women up to age 65
years appear similar to the rates found in the current
study for unexposed women. A case-control study of
fracture and DMPA use found adjusted odds ratios for
DMPA use between 1.18 (95% CI 0.931.49; one to
two cumulative prescriptions) and 1.54 (95% CI 1.33
1.78; 10 or more prescriptions).19 Although fractures
likely to be trauma-related (leg, foot, hand) were associated with DMPA in that study, spine and hip fractures (potentially related to low BMD) were not.19 A
second case-control study of fractures and use of
DMPA or IUD reported adjusted odds ratios of 1.44
(95% CI 1.012.06) for DMPA use and 0.75 (95% CI
0.640.87) for IUD use, but the authors acknowledged
that unassessed confounders may have affected the
results.20 A prospective, nonrandomized study examined risk factors for stress fracture among female army
recruits.21 Smoking and excessive alcohol intake were
associated with an increased incidence in fractures,
but contraceptive use showed no important association, except for DMPA use in a subcohort of nonHispanic white women (incidence rate ratio 1.71,
95% CI 1.012.90).21 No studies, however, have
examined fracture incidence before DMPA use.
There were several notable findings in this study.
Although DMPA users had higher fracture risk than
nonusers, risk did not increase after starting DMPA
but was similarly present before DMPA was initiated.

OBSTETRICS & GYNECOLOGY

Table 5. Incidence Rate Ratio for Fracture by Ever-Use of Depot Medroxyprogesterone Acetate and Codes
for Fracture Site in the Full Cohort
DMPA User
(327,315 Person-Years)
Fracture site*

No. With
Fracture

Axial (vertebrae, hip,

and pelvis)
Appendicular skeleton
(arm, leg, wrist, ankle,
hand, foot, clavicle, rib
or sternum, and shoulder)
All other fractures (eg, finger,
toe, skull, face, multiple
trauma, and unspecified)
Total

73
1,624

1,238

2,935

Fractures/1,000
Person-Years
0.2
5

3.8

DMPA Nonuser
(1,395,041 Person-Years)
Fractures/1,000
Person-Years

Crude Incident
Rate Ratio (95% CI)

327

0.2

0.95 (0.741.23)

5,012

3.6

1.38 (1.311.46)

3,548

2.5

1.49 (1.391.59)

8,887

6.4

1.41 (1.351.47)

No. With
Fracture

DMPA, depot medroxyprogesterone acetate; CI, confidence interval.

* Fracture site is based on Read and Oxford Medical Information System coding in General Practice Research Database data.

Unadjusted rates.

Only symptomatic vertebral fractures would have been reported to the General Practice Research Database.

A total of 1,906 fractures (39.8% of the total fractures in this row) occurred at unspecified bone sites.

This comparison controlled for confounders not measurable in the General Practice Research Database but
that probably remained constant over time within
a woman. Risks for hip and vertebral fractures are
particularly sensitive to BMD changes and routinely
serve as primary endpoints in randomized osteoporosis
trials, whereas finger, toe, face, and skull fractures
typically are not analyzed in these trials22 because their
incidence does not correlate with BMD changes
because these fractures probably result from trauma.10,17
Therefore, although few if any true fragility fractures
would have been expected in this study, because of
the young mean age of the women, we found no difference in risk for axial fractures (hip, symptomatic vertebral, or pelvic fractures), along with the largest
incidence rate ratio being finger, toe, face, or skull fractures. This is consistent with the overall higher fracture
incidence in DMPA users being unrelated to a decrease
in BMD, but possibly it is attributable to differential
risks for traumatic injury. Neither the time trend for
fractures after DMPA started nor the trend with cumulative DMPA exposure fits a pattern that is consistent
with a causal effect of DMPA. Fracture rates were
greater in DMPA users immediately on beginning contraceptive use as well as before beginning. Furthermore,
longer-term DMPA users had a lower fracture risk than
shorter-term users, which would be unexpected if the
higher fracture risk among DMPA users was related to
an adverse effect of DMPA on bone.
A limitation of our study is the possibility of
uncontrolled confounding by factors for which we had

VOL. 121, NO. 3, MARCH 2013

no data (eg, education level, participation in sports or

other risk-taking behaviors of a physical nature, and
attitudes toward contraception) or for which we had
incomplete data (eg, body mass index and smoking
history). Confounders also may have been misclassified, through inaccuracy in recording medical history
or through missing data, and thereby reduced the
ability to control for differences in such factors
between the exposure groups.
Some studies have reported important baseline
differences between women self-selecting DMPA and
women choosing other prescription contraceptive methods, including lower socioeconomic status and educational attainment,1 as well as differences in risk factors
for falls, fractures, and osteoporosis.20 In one prospective study of the effects of DMPA on BMD, important
differences precluded a planned postbaseline comparison between the DMPA user and nonuser cohorts.23
Although the potential confounders measurable in the
current study did not have confounding effects, the
results suggest that unassessed factors, possibly related
to behavior, lifestyle, or unreported medical history,
differed between cohorts and could be the underlying
cause of the higher fracture risk in the DMPA cohort.
Reporting bias also may have affected the results. Visits
every 3 months by current DMPA users may have
enabled more accurate fracture reporting, whereas nonusers or past users generally visit less often.
In conclusion, the overall findings of this study
demonstrated that DMPA use was associated with
greater fracture risk compared with nonuse, both

Lanza et al

DMPA and Bone Fracture

599

before and after DMPA use began. Although reversible decreases in BMD are well-documented with
DMPA, the current findings do not suggest that these
BMD decreases had any clinically important effect on
fracture risk during study follow-up (mean was
approximately 6 years). The association between
DMPA use and higher fracture risk does not appear
to be the result of a causal effect of DMPA but may
represent inherent differences in fracture risk between
women who elected to use DMPA and women who
used other prescription contraceptives.
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