The document is a capstone report analyzing the relationship between the contraceptive Depo-Provera and bone mineral density (BMD) in adolescent females. It highlights that Depo-Provera, while effective for birth control, is associated with significant bone loss in young users and raises concerns about prescribing it without age restrictions. The report calls for caution, recommends osteoporosis risk assessments before prescription, and notes the need for further research on long-term effects and strategies to mitigate bone loss.

1. Depo­Provera: It’s Detrimental Effects on Bone Health
Should there be an age restriction on its prescribing to teens
who have yet to reach optimal bone mineral density?
Jessica Brown B.S. RT (R)(M)
Capstone Advisor: Don Allensworth­Davies, PhD, MSc
Reader: Stella Iwuagwu, PhD, MPH, RN
Final Capstone Report for Master’s of Science in Health Sciences Program
School of Health Sciences, Cleveland State University
April 22, 2014

3. ABSTRACT
Much effort has been made within the last decade to educate the public and raise
awareness about bone density and preventing osteoporosis, yet it is common practice to
prescribe a drug to teens that is known to cause a loss in bone mineral density (BMD).
Depo­Provera is a very popular birth control method among teens and a major side effect
of DMPA is bone loss. Because teens and young adults have yet to reach peak bone
mass, this medication could affect their bones later in life if not now. Should there be an
age restriction on its prescribing to teens?
Objective: A systematic review of relevant literature over the past decade on the
relationship between Depo­Provera (DMPA) and bone mineral density (BMD) in
adolescent and young adult females. Methods: Searches were performed in PubMed and
OhioLink EJC resulting in a review of 15 articles. Findings: Research reiterates the
findings of adverse effects of DMPA on BMD in this special population that has yet to
reach skeletal maturity and analyzes ways to reduce bone loss including estrogen, calcium
and/or Vitamin D supplementation, while other studies attempt to measure bone
remineralization after discontinuation of use. Conclusion: Much research needs to be done
pertaining to long term effects of DMPA, preventing bone loss and bone remineralization.
Recommendations: Until more can be learned, DMPA should be prescribed with caution
to this population and an osteoporosis risk assessment should be performed before
prescribing. High risk patients should be educated on bone health, have DEXA scans to
monitor BMD, and be limited to two years of use.

4. INTRODUCTION
Much effort has been made within the last decade to educate the public and raise
awareness about bone density and preventing osteoporosis, yet it has become common
practice to prescribe a drug to teens that is known to cause a loss in bone mineral density
(BMD). On October 29, 1992, the FDA approved Depo­Provera Medroxyprogesterone
Acetate (DMPA) (FDA, 2013). DMPA is a long term progestin­only
Gonadotrophin­releasing hormone agonists (GnRH) prescribed frequently to teens and
young women for birth control (WebMD, 2013). It is a highly effective, injectable medication
that lasts 11­ 15 weeks. According to the Surgeon General’s Report on Bone Health and
Osteoporosis, DMPA causes levels of bone loss that are similar to that seen in women
after menopause (Office of the Surgeon General, 2004). DMPA has carried a black box
label since 2004 warning users of the risk of significant loss in bone mineral density which
may be irreversible and could increase the risk of osteoporotic fractures later in life (RX
List, 2013). The label points out that using this medication during adolescence or early
adulthood during a critical period of bone accretion will reduce bone mass and should not
be used as a long term birth control method (Cromer et al., 2008)
This information raises the question whether an adolescent with lower than normal
bone density can ever “catch up” and have healthy bones through adulthood and maintain
adequate bone density through menopause, and whether it is safe, acceptable or even
ethical to prescribe to young women and adolescent girls a birth control medication that
essentially halts bone mineralization before full bone mineralization is achieved.
Importance for Health Research

5. Osteoporosis is the thinning of bone tissue resulting in weakened bones; essentially
bone reabsorption occurs faster than bone mineralization. Low BMD (osteoporosis or
osteopenia) is a serious health condition that increases a person’s risk for osteoporotic
fractures (usually of the hip, wrist or compression fractures of the spine) and can have
devastating effects on one’s quality of life (Johnell & Hertzman, 2006). In the past,
osteoporosis was thought to be a natural process of aging and was only considered in the
elderly population; however it is now recognized as a serious and usually preventable
debilitating disease that affects people of all ages for various reasons (Stetzer, 2011).
“Because of related morbidity and disability, diminished quality of life, and mortality,
osteoporosis and the fractures associated with it are major public health concerns. The
worldwide prevalence of disability from hip fractures alone is projected to be close to 2.6
million by 2025, and deaths following hip fractures have been projected to be about
700,000 per year by the year 2025” (Office of the Surgeon General US, 2004).
Osteoporosis is considered a silent disease because there are no real signs or
symptoms until the disease has already severely affected the bones. Symptoms include
loss of height, development of a curved upper back (Dowager's Hump) or an osteoporotic
fracture (Johnell & Hertzman, 2006). When symptoms appear it is too late for prevention.
Currently the only way to screen for osteoporosis is through a diagnostic radiological exam
called a Dual Energy X­Ray Absorptiometry Scan (DEXA) which measures bone mineral
density (WebMD, 2013).
The significance of bone health during puberty is well known. The Surgeon General

6. states the amount of BMD gained during puberty usually equals the amount lost through
adulthood. Achieving (or not achieving) optimal bone mass during puberty allows for (or
doesn’t allow for) a reserve of bone mass that will be necessary for normal bone loss later
in life (Office of the Surgeon General, 2004). Ninety percent of adult bone mass is
obtained within the first 20 years of life and the detriments and benefits of that bone health
will be seen throughout life (Moretto, et al., 2011). In fact, up to 50% of total body bone
mass occurs between the ages of twelve and eighteen (Cromer et al., 2008).
METHOD OF SYSTEMATIC REVIEW
Information Sources and Databases
PRISMA guidelines were used as a framework (Moher et al., 2009) and all articles
used in this systematic review were located through database searches of online peer
reviewed scientific articles or journals. All searches had limiters to only include studies
involving humans that were published within previous 10 years (2003­2013). An electronic
search strategy was used and articles were identified from the National Center for
Biotechnology Information (NCBI) via PubMed.gov and through OhioLink via the Electronic
Journal Center (EJC).
Search Terms and Criteria for Selected Articles
Each of the following terms were entered into the search boxes in different
combinations to ensure all relevant articles were located. The Medical Subject Headings
(MeSH) terms used were: Adolescent; BMD; Bone Mineral Density; Depot
Medroxyprogesterone Acetate; DMPA; DEXA (Dual Energy X­ray Absorption); and
Postmenarcheal. The eight possible combinations were then entered into each database,

7. the resulting articles were compared and duplicates were eliminated. Many articles were
eliminated based on their title and/or abstract because they were inappropriate for this
review.
Table 1. Sample Search and Article Yield
PubMed Through NCBI
U.S. Library of Medicine
EJC (Electronic Journal
Center) OhioLink
Cross­referenced with
PubMed
Adolescent + DEXA +
medroxyprogesterone
acetate
1 0
Adolescent + BMD +
medroxyprogesterone
acetate
22 19
Adolescent + DEXA +
DMPA
1 0
Adolescent + BMD +DMPA 18 16
Postmenarcheal + DEXA +
medroxyprogesterone
acetate
0 0
Postmenarcheal + BMD +
medroxyprogesterone
acetate
3 4
Postmenarcheal + DEXA +
DMPA
0 0
Postmenarcheal + BMD +
DMPA
3 4
Total 48 43

8. Figure 1. PRISMA Flow Diagram
Inclusion/Exclusion Criteria
Study designs represented are quantitative and systematic reviews. After articles were
found, they were screened against the inclusion/exclusion criteria:
● Previous studies conducted on teen and young women ages 12­21 who had

9. self­chosen to use Depo­Provera for any reason.
● Study length of at least 24 months.
● Prior studies must have measured baseline bone mineral density (BMD) with Dual
Energy X­Ray Absorptiometry (DEXA) and follow up scans at pre­determined
intervals.
● Prior studies should have occurred in an outpatient setting with healthy individuals.
● Studies involving individuals with prior bone health issues including but not limited to
osteoporosis, Paget’s disease, osteoarthritis, osteogenesis imperfecta,
rheumatoid arthritis, bone cancer, or leukemia were excluded, as well as studies
with subjects using medications known to affect bone density including chronic
cortico­steroids, albuterol inhalers or bone enhancing medications such as Boniva.
● All studies included took place within the last 10 years (2003­2013).
● Prior studies must have been performed in scientific format, were peer reviewed,
the full text was retrievable, and were written in English.
Table 2. Summary of Included Studies
Source Setting Number
Subjects
Age
Range of
Subjects
Inclusion Criteria
1 Busen et al., J
Adolescent Health,
2003
Outpatient 22 15­19 Depo­Provera; BMD
measured with DEXA
2 Lara­Torre et al., J Outpatient 148 11­21 Depo­Provera; BMD

10. Pediatr Adolesc
Gynecol, 2004
measured with DEXA
3 Rome et al., J Pediatr
Adolesc Gynecol, 2004
Outpatient 370 12­18 Depo­Provera; BMD
measured with DEXA
4 Cromer et al., J
Adolescent Health,
2004
Outpatient 215 12­18 Depo­Provera; BMD
measured with DEXA
5 Cromer, B., Clin Rev
Bone Miner Metab,
2004
N/A
Literature
Review
N/A N/A Previous 10 years
relationship between
DMPA and BMD
6 Beksinska et al.,
Contraception, 2007
Outpatient 490 15­19 Depo­Provera; BMD
measured with DEXA
7 Cromer et al., Fertil
Steril, 2008
Outpatient 433 12­18 Depo­Provera; BMD
measured with DEXA
8 Johnson et al.,
Contraception, 2008
Outpatient 389 11­18 Depo­Provera; BMD
measured with DEXA
9 Beksinska et al.,
Contraception, 2009
Outpatient 490 15­19 Follow up of #6
10 Harel et al., J Pediatr
Adolesc Gynecol,
2010b
Outpatient 15 12­18 Depo­Provera; BMD
measured with DEXA
11 Harel et al.,
Contraception, 2010a
Outpatient 98 12­18 Follow up of #8
12 Harel et al.,
Contraception, 2010c
Outpatient 181 12­18 Follow up of #8
13 Bonny et al., J Pediatr
Adolesc Gynecol, 2011
Outpatient Not given 12­18 Depo­Provera; BMD
measured with DEXA
14 Nappi et al.,
Contraception, 2012
Systematic
Review
N/A N/A Effects of hormonal
contraception on
bone metabolism
15 Zhang et al., Chin. Med.
J, 2013
Not
mentioned
199 16­18 Depo­Provera; BMD
measured with DEXA

11. Methods Used to Assess Bias in Articles
To avoid bias, it is imperative that all articles/studies reviewed on this topic are
found and analyzed against the inclusion/exclusion criteria, and are reported accurately.
The Cochrane Collaboration tool for assessing risk of bias was used to assess each
article for overall strength of evidence. The Cochrane tool is extremely comprehensive and
evaluates seven specific domains: sequence generation, allocation concealment, blinding
of participants and personnel, blinding of outcome assessment, incomplete outcome data,
selective outcome reporting and ‘other issues’ (Higgins JP, et al. 2011). The results from
the tool are then categorized as high risk of bias, low risk of bias, or unclear risk of bias.
Only articles that were categorized as low or unclear risk of bias were included in this
review. See the Cochrane Collaboration Article Bias Tool in Appendix B.
RESULTS
Summary of Information Extracted from Articles
The key elements and information that was extracted from all of the articles in this
review include the results of studies done on DMPA and its effects on BMD in adolescent
females before full bone mineralization has occurred, other contributing factors to the loss
of BMD in adolescents taking DMPA, and information on the rate of bone remineralization
after cessation of DMPA. In line with the inclusion criteria, all studies performed a
measurement of BMD through the use of DEXA scans. Most scans were performed on the
hip (femoral neck) and spine, while two measured the forearm (Beksinska, Kleinschmidt,
Smit, & Farley, 2007; Beksinska, Kleinschmidt, Smit, & Farley, 2009). Changes in BMD
were more notable in studies of the hip and spine. It may be that differences in BMD are

12. more sensitive to the hip and spine and decreases would be magnified at those sites
(Beksinska et al., 2007).
In 2003, studies were aiming to determine if there was in fact a negative effect on BMD
in DMPA users as compared to controls as had been suggested in earlier studies. Also,
earlier studies were mostly on adult women so studies on adolescents were still emerging.
In 2003, 24 month prospective study with hip and spine DEXAs done at baseline, 12
months and 24 months was performed. At the end of year one, significant mean bone loss
in the femoral neck was 3.31% and 3.52% in the lumbar spine and trends continued
through to 24 months (Busen, Britt, & Rianon, 2003). However only 4/22 participants
completed the study. In another study, results showed a steady decline in BMD in the
DMPA group from baseline. At 6 months ­3.01%, 12 months ­3.02%, 18 months ­4.81%
and 24 months ­6.81%, and there was no statistical difference between pills and control
(Lara­Torre, Edwards, Perlman, & Hertweck, 2004). Then researchers began to
investigate the reasons for the loss in BMD. Studies continued to include DEXA scans but
also studied other factors affecting bone density in adolescents, including estrogen levels,
BMI, calcium intake, and Vitamin D deficiency. Studies emerged that measured mixed
contraceptives as well therefore allowing participants to stay in the study if they switched
methods.
In 2010, a study categorized DMPA users into two groups: users with more than 5%
loss and those with less than 5% loss to determine biopsychosocial variables between the
groups. The most significant factor affecting BMD was number of DMPA injections but it
was determined that the associated bone loss could possibly be controlled by managing

13. secondary factors including calcium intake, BMI, and alcohol use (Harel, Wolter, Gold,
Cromer, Stager et al., 2010c). In another study, it was determined that regardless of the
method chosen (DMPA, OC, or none) body weight was positively correlated with hip and
spine BMD suggesting that weight gain on DMPA may mitigate bone loss in adolescents
(Bonny, Secic, & Cromer, 2011). DMPA use induces a state of estrogen deficiency (Harel,
Wolter, Gold, Cromer, Bruner et al., 2010c). Estrogen is a very important hormone for
regulating bone mass. Decreasing circulating levels of estrogen has a significant impact
on bone and future peak bone mass (Cromer et al., 2004). It is of utmost importance during
periods of growth as the bones must grow thicker as they grow longer. In women, estrogen
levels fall significantly after menopause inducing a fast resorption of bone tissue (Nappi et
al., 2012). DMPA and other hormonal contraceptives reduce estrogen levels and thereby
induce a state of menopause virtually halting bone mineralization.
Most of the studies reviewed support the theory that DMPA is associated with a
decrease in BMD however, “data on DMPA use and fracture risk are still unclear…and it is
still unclear if adolescents can reach peak bone mass after discontinuation of DMPA
(Nappi et al., 2012). In contrast, the American College of Obstetricians and Gynecologists
stated that current evidence suggests that partial or full recovery of BMD occurs at the
spine and at least partial recovery occurs at the hip after discontinuation of DMPA (ACOG
Committee Opinion No. 415, 2008). Estrogen deficiencies also affect intestinal calcium
absorption which is particularly important in DMPA users with low calcium intake from their
diet (Harel et al., 2010b). Still, there are other methods of measuring bone activity. Serum
bone specific alkaline phosphate (BSAP) is produced by osteoblasts, the cells which build

14. bone, and can be used to measure bone formation with biochemical markers. One study
attempted to discover a relationship and found there was evidence of increased bone
formation and resorption in the control group when compared to the DMPA and OC groups
(Rome et al., 2004). Vitamin D is another factor affecting BMD because it works with
calcium and estrogen to help build bone. A 2010 study took blood samples to measure
Vitamin D in subjects who had more than 5% BMD loss (as measured with DEXA at the
hip and spine). One out of 15 (7%) had sufficient Vitamin D levels, (50%) had Vitamin D
insufficiency, and (43%) were deficient in Vitamin D (Harel et al., 2010b). Baseline Vitamin
D tests were not obtained however, so it is unclear if the low Vitamin D contributed to the
low BMD.
It became evident that long term studies following the cessation of DMPA were needed.
In 2010 A multi­center, prospective, non­randomized observational study on participants
who provided BMD for up to 240 weeks while using DMPA and for up to 300 weeks after
discontinuation of DMPA. DEXA of the hip and spine were obtained. The results of this
study suggest that BMD loss in female adolescents receiving DMPA is substantially or fully
reversible in most girls following discontinuation results showing that 84% had spine BMD
that exceeded their baseline value at 240 weeks after discontinuation (Harel, Johnson et
al., 2010a), however data excluded what the expected BMD should have been at that point
had they never used DMPA (greater than baseline). In 2013, a 24 Month prospective study,
hip and spine DEXAs were done at Baseline, 12 months, and 24 months. Throughout the
study, the DMPA group showed a steady decline in BMD. At 24 months the change from
baseline for the spine and hip was ­1.88% and ­2.32% respectively. However the

15. non­users showed an increase of BMD and at 24 months the change from baseline for the
spine and hip was +1.80% and +.85% respectively (Zhang MH, Zhang W, Zhang AD, Yang
Y, & Gai L, 2013).
In 2012, Nappi et.al, performed a systematic review to analyze the overall effect on
BMD in the general population and on fracture risk of COC (combined oral contraceptives),
progestogen­only contraceptives (includes DMPA), transdermal contraceptives, and
vaginal ring. The studies reviewed by Nappi, et al strongly suggested DMPA is associated
with a decrease in BMD, but data on DMPA use and associated fracture risk was limited
(Nappi, Bifulco, Tommaselli, Gargano, & Di Carlo, 2012).
DISCUSSION
Many of the studies examined had significant limitations which were reported. Due
to the nature of the age group being studied, gathering long term information on
adolescents taking any form of birth control is a challenge due to high dropout rates
whether because of lack of compliance, change of method and/or pregnancy. However,
even with high attrition rates, the information gathered must be analyzed and new studies
must be put into action.
DMPA is an extremely popular birth control method, especially among teenagers
who possibly could not comply with daily contraceptives or methods that must be used with
each act of intercourse. The possible adverse side effects have to be carefully weighed
against unplanned pregnancy by the patient and physician.
It is apparent that DMPA use causes a significant decline in BMD in adolescents

16. when BMD should be increasing. What is unclear is whether or not the bones can fully
recover from such loss in order to withstand other losses later in life that are inevitable (i.e.
aging). More studies following the use and discontinuation of DMPA are needed in this
area. It is also clear there are many factors that affect bone health and that some of those
factors are manageable with diet, exercise and supplements. Estrogen levels can be easily
measured, and more studies are needed to determine if calcium and/or Vitamin D
supplementation can slow the rate of bone loss.
Fracture risk is a very important consideration when discussing BMD. If the
reduction in BMD doesn’t cause increase of fracture risk for teens, and it is proven that
BMD levels do in fact return to normal, then the side effect of low BMD is insignificant and
warning labels could be removed. However, if the opposite is found and DMPA users (or
recent users) have more fractures than their peers, or it is determined that BMD never fully
recovers and those women experience more osteoporosis as they age compared to their
peers, an age restriction should be imposed on the prescribing of DMPA. If research to
prevent bone loss by supplementing calcium, Vitamin D and/or estrogen and long term
effects are proven to be adverse, changing the age at which DMPA is prescribed will result
in significant health improvements. The question remains whether should there be an age
restriction for the prescribing of DMPA to adolescents and young women before they reach
the age of full bone mineralization, thereby possibly reducing their chance of developing
osteoporosis in their lifetime.
RESEARCH RECOMMENDATIONS
1. Long term research studies are needed to determine if the bones of adolescents can

17. fully recover from such BMD loss in order to withstand loss later in life.
2. Studies are needed to determine if calcium, Vitamin D and/or estrogen
supplementation slow the rate of bone loss in this population without imposing other
negatives side effects such as increased risk of breast cancer.
3. The key research issue that needs to be addressed is fracture risk. Fracture is the
main cause for concern in patients with low BMD.
CLINICAL RECOMMENDATIONS
Until further research is completed, DMPA should be prescribed with caution. If a
patient is inclined to start DMPA, an osteoporosis risk assessment should be performed.
High risk patients should be screened and monitored for low BMD.
1. Screening for osteoporosis risk before prescribing Depo­Provera
● History of bone disease?
● Family history of osteoporosis?
● Smoke cigarettes?
● Drink alcohol?
● History of fractures?
● Low dietary calcium intake?
● Take other medications that affect bone health?
2. Management of high risk patients who opt to use DMPA
● Educate patient on bone health and side effects of DMPA
● Obtain a baseline DEXA scan.
● Offer other options for birth control such as the pill.
● Limit use to two years.
● Instruct patient to take calcium and vitamin D supplements if appropriate.
3. Follow­up

18. ● Order DEXA scan every 6­12 months until BMD returns to baseline.
CONCLUSION
Although this research question was not answered, more questions were raised and
the need for more research was highlighted. The recommendations Cromer, et al made
after a systematic review of studies from 1993­2003 are still appropriate today: “several
issues needed to be considered in evaluating prescription of DMPA and oral
contraceptives (OCs) in young women including: (1) likelihood of at least partial recovery of
BMD after cessation of contraceptive method; (2) the short duration of use common among
young women, thereby self­limiting loss; (3) the real need for and benefit of effective and
appealing contraceptives in this age group; and (4) the feasible management approach
that appears to ameliorate the problem, i.e., adding estrogen supplementation, in those
receiving DMPA” (Cromer et al., 2004).

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Stetzer E. (2011). The Internet Journal of Allied Health Sciences and Practice. Identifying

23. Risk Factors for Osteoporosis in Young Women and Practice. Volume 9 Number 4.
Retrieved from: http://ijahsp.nova.edu/articles/Vol9Num4/pdf/Stetzer.pdf
WebMD website (2013). Osteoporosis Health Center. Retrieved From
http://www.webmd.com/osteoporosis/default.htm
Zhang MH, Zhang W, Zhang AD, Yang Y, & Gai L. (2013). Effect of depot
medroxyprogesterone acetate on bone mineral density in adolescent women. Chin
Med J (Engl)., Nov(126(21)), 4043­7­PubMed PMID: 24229671.

24. APPENDIX A:
Data Extraction List:
● Author (s)
● Title
● Database
● Name of journal
● Objective/Goal
● Inclusion Criteria
● Exclusion Criteria
● Include? Y/N
● Type and length of research/methodology
● Number of Subjects
● Age range of subjects
● Setting
● Actual Findings
● Reported Findings
● Support Vs. Challenge
● Limitations
● Link/DOI/PubMedID

25. APPENDIX B:
Cochrane Collaboration Article Bias Tool
Higgins JPT, Altman DG, Sterne, JAC (editors). Chapter 8: Assessing risk of bias in included
studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of
Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available
from www.cochrane­handbook.org