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

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.

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

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

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,

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

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

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

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

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

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

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

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

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

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

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

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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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

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