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Depo Provera Use and Bone Health

New science decreases concerns even about use in teenagers

by Drs. Azita Goshtasebi & Jerilynn C. Prior

Many teenagers and women of all ages around the world use a three monthly injection of medroxyprogesterone for contraception. This long-acting and highly effective birth control method is officially called DepoProvera® but for simplicity here we will call it “Depo”. Depo is a high-dose synthetic progestin (progesterone-like chemical) given as an injection every three months (1). There are real concerns that Depo may be bad for women’s bone health because Depo causes bone loss (2, 3). In the long term this might increase a woman’s risk for bone fractures (breaks). Use of Depo is a particular concern for teenagers because it might prevent young women from gaining their optimal, peak or highest lifetime bone density (4).

In light of these concerns, in November 2004, the US Food and Drug Administration (FDA) placed a “black box warning” on Depo with two highlights:

  1. Prolonged use may be associated with considerable loss of bone mass especially in adolescent girls,
  2. Bone losses may not be completely reversible after stopping Depo Provera.

Since scientific evidence to support this warning were not sufficient, the Society for Adolescent Medicine reviewed the available evidence in 2006 and suggested new guidelines for clinicians who provide care for adolescent girls (5). They recommended that Depo could be used by adolescent girls for contraception with an appropriate explanation of benefits and risks. They also advised that Depo could be used for more than two years. Finally they suggested that teenagers on Depo should make lifestyle changes such as taking at least 1300 mg a day of calcium and 600 IU of vitamin D every day plus doing regular physical activity. We appreciate that often teens will have a hard time following those recommendations (just like they may have a difficult time taking “the Pill” every day). The US FDA has not yet removed the black box warning despite increased and reassuring information about Depo and bone health that we are sharing here.  
The purpose of this article is to describe what is known about changes in bone health (bone density and fractures) when adolescent and other menstruating women choose to use Depo for contraception. To understand this we first need some background on peak bone density, how bone renovates and balances itself and how menstrual cycle hormones are related to bone balance.

How old are we at Peak Bone Density?

Bone density is measured using a kind of “bone scan” (usually called DXA) that tells us the amount of calcium and other minerals that are in a particular size of bone. Bone mineral density is an important indicator of bone health. A decreased bone density may mean that the bone is also less strong and at increased risk of breaking. Peak bone density occurs at different ages in different bones in our bodies and our best evidence related to it is from studying whole populations as the Canadian Multicentre Osteoporosis Study does (www.camos.org). Although 95% of peak bone density in the spine bone (back bone) occurs during the teen years, the final peak isn’t reached until ages 33-40. For the hip bone and a small region within the hip known as the femoral neck (where serious hip fractures occur) peak bone density occurs before or during ages 16-19 (6). It is very important for young women to reach their highest possible peak bone density during their teenage years and early adulthood because this helps reduce the risk of very low bone density and fractures in perimenopause and menopause (when bone loss becomes normal).

How can I gain a high Peak Bone Density?

Things that create a strong peak bone density besides being healthy include almost everything about us—but being a full-term baby and growing normally in childhood help. Being physically active, having a good diet that includes calcium, vitamin D and minerals (milk and dairy foods are good sources) and protein and being “easy going” (or with adequate support and a positive social environment) are all important (7). The age of a woman’s first period is also important—if a woman doesn’t get her first period until she is older than 14 years she will usually have a lower peak bone density than a woman who got her first period before age 14. We also know that the sooner in adolescence a young woman develops a regular month-apart ovulatory (egg-releasing with enough progesterone) menstrual cycle is likely important. Women with normal cycles and ovulation are more likely than those with ovulatory disturbances to be emotionally, socially and physically healthy. Women who are disadvantaged (in lack of education or health care, by social inequities and by violence or abuse) are likely to have lower bone density and to lose bone more rapidly. A quick summary of the things that help us have good bone health can be found here

How is Adult Bone Density Balanced?

Throughout adulthood our bones are constantly undergoing a renovation process. Special bone cells take away old or damaged bone and rebuild new bone and this process is called bone remodelling or “bone turnover.” Bone turnover happens in very small special sections within all bones (but most rapidly in the spine and ribs). Two types of cells in bone contribute to this process. Osteoclasts are big cells (related to blood cells) made in the bone marrow that take out bone either because the bone is old (and damaged) or because calcium is urgently needed (like when a woman is breastfeeding). Osteoclasts work very quickly so in any one small spot inside our bones their work is over in three weeks. Osteoblasts are tiny specialized cells also from the bone marrow (related to muscle and fat) that are responsible for making the protein of new bone tissue into which calcium and other minerals are added (mineralization). Unlike osteoclasts, osteoblasts are slow and meticulous taking three months to fill up the hole that the osteoclasts just made. This is like renovating your kitchen—it takes no time at all to remove the cupboards, sink and stove (and make a big mess!) but it takes forever before the new floor and cabinets are installed and the kitchen is equipped and back to use. Bone turnover is an ongoing process of bone resorption (by osteoclasts) and formation (by osteoblasts). The two processes are in balance to maintain a steady bone density.
Once we achieve peak bone mineral density we need to keep bone strong until we start skipping menstrual cycles later in perimenopause when it becomes normal to lose bone.

Bone density over lifespan     

Adult bone density (and the actions of osteoclasts and osteoblasts) is controlled by many things related to how we live our lives, what we eat and how active we are. We are still in the process of learning the balance of all of these factors. To reduce the risk of developing osteoporosis and fractures later in life, it is important to keep a healthy lifestyle (avoid smoking and excess alcohol and do moderate activity for half an hour a day), eat a balanced diet and be cautious about bone-negative medications (like prednisone and the SSRI-type anti-depressants) (8-10).

How do Bone Density Changes relate to Menstrual Cycle Hormones?

Most hormones (chemicals made in a gland that travel through the blood stream to have actions in other parts of the body) are related to bone turnover either in positive or negative ways. For women’s hormones we will focus on estrogen and progesterone.
During the normal menstrual cycle (to keep a complex process simple) the ovaries make two main hormones, estrogen and progesterone. They have normal patterns that look like the Figure below:  Estrogen is primarily the hormone for preventing bone loss. It indirectly slows the number of spots in bone where osteoclasts are active and decreases the amount of bone that osteoclasts remove. Progesterone is the hormone for building new bone. Progesterone directly stimulates more osteoblasts to be formed and increases the amount of bone that each osteoblast builds. When estrogen levels decrease, even briefly, however, this is a powerful signal leading to bone resorption (loss). 

 Normal menstrual cycle

If you look again at the menstrual cycle diagram you will see that estrogen levels rise to a peak during the middle of the cycle, decrease a bit around egg release (middle of the cycle) and rise slightly during the luteal phase before dropping to low levels again before flow. Bone resorption (loss) is therefore low as estrogen levels rise but will increase as estrogen levels decrease toward the end of the cycle. Progesterone and ovulation are needed to provide bone formation and balance the bone loss caused by the normal drop in estrogen levels toward the next flow. A study of bone density in about 500 premenopausal women discovered that women with the lowest bone density had the lowest menstrual cycle levels of progesterone (11). A meta-analysis (a study that combines the results of many studies) of bone changes and menstrual cycle and ovulation changes over years found that women (with regular periods) within each study who had worse ovulation (and were making less progesterone) were losing, on average, almost one percent more spinal bone density a year than those with better ovulation (12). Therefore for keeping strong bones until perimenopause and menopause we need to have both normal estrogen and progesterone levels. We need regular and ovulatory menstrual cycles.

How does Depo Change Menstrual Cycle Hormone Levels?

Depo is an injection of a high dose of progestin, medroxyprogesterone acetate, which is a synthetic chemical like progesterone. The progestin “talks back” to the hypothalamus and pituitary gland (which secrete hormones) and suppresses the signals that usually coordinate the normal menstrual cycle. Depo prevents pregnancy by making estrogen levels drop to moderately low levels and by stopping ovulation (but provides a synthetic hormone that acts like progesterone in osteoblast bone building). Depo causes bone loss during the first year or two after a woman of any age starts taking it. Why? Estrogen levels decrease and usually cycles become less frequent and often stop. As we talked about, dropping estrogen levels always cause bone loss. We know for sure that the drop in estrogen levels is the cause of the bone loss because controlled studies have given some women on Depo a low dose of estrogen and other women on Depo a sugar pill; the results showed that bone loss was prevented in women who took Depo plus estrogen (13). While talking about bone loss in Depo users, other lifestyle factors should not be forgotten. For example, smoking and excess alcohol consumption both harm bone health. Comparing Depo users and nonusers, women who decide to use Depo often have more bone risk factors (more past broken bones, are more likely to smoke, to have risky alcohol and other drug use and to be socially and emotionally disadvantaged) (14). Therefore, the changes in bone density cannot be completely related to Depo in this group of teenagers.

What do we know about Depo and Bone Density in Teenagers?

Several researchers have studied the relationship between Depo and bone health in girls and young women. In a study from Seattle that matched about 100 young women ages 14 to 18 taking Depo, or just starting it, with young women not taking contraception showed that over two years young women taking Depo lost about two percent (1.8%) of their hip bone mass compared with almost no change in the non-Depo taking teens. Young women on Depo also lost about one percent of their spine bone density while those not on Depo gained bone density (about one percent a year) (15). However, when the Seattle teen women stopped Depo and had bone density carefully measured over one or two more years, they gained bone density in the hip and spine. They gained significantly more bone density at every measurement site than the teen women not on contraception. The authors’ reassuring summary is that Depo-related “bone loss is regained, even in younger users.” (15). This observation was confirmed in a multicentre study in almost 100 adolescent women who had bone density measured while taking Depo and for several years after they stopped it (16).
We’ve already figured out that the drop in estrogen levels caused by Depo increases bone resorption that leads to bone loss. Now we have a new question:

Why is there Regain of Bone Density when Women Stop Depo?

We don’t know for sure but we believe there are two reasons why women gain bone when they stop using Depo. One reason is that when women stop using Depo their estrogen levels rise, their periods return and this stops osteoclasts from causing further bone loss. The second reason is that medroxyprogesterone is similar enough to progesterone that it stimulates osteoblasts to build new bone. After discontinuation of Depo, the blood level of the progestin remains high for a few months and then gradually goes away. During this time, (hopefully) menstrual cycles become regular again and then ovulation and progesterone production begin again. When Depo is stopped the higher estrogen levels slow bone loss and the actions of the progestin increase bone formation. These two changes together cause an important increase in bone density.
Evidence suggests that those who have ever used Depo (non-Depo related factors being equally healthy) may end up with a bone density like that or even higher than the bone density of similar-aged teens who have never used Depo (16). It does take much longer (several years) for hip bone density to recover than for spine bone density, however.

What about Depo use and Bone Density Changes in Young Adults?

When women in their 20-40s use Depo for contraception they also lose bone density in similar amounts as teenagers. However, research results show that the controls (non-Depo users) are no longer gaining bone (17). As in teenagers, bone loss is greatest in the first two years after starting Depo and after that bone loss slows so that the rate of bone change is the same as in women not using Depo (18, 19). Like in teenagers, over time and especially if the women’s cycles become or return to being regular, normal length and ovulatory after stopping Depo, there will be no overall negative bone density change from the past use of Depo for two or more years. Results of a large well designed study showed that in young women who start “birth control pills” (combined hormonal contraception, CHC) after discontinuation of Depo, bone density recovered in the spine but not in the femoral neck (20). This emphasizes the importance of having or recovering normal ovulatory cycles for healthy bones.
Bone health is an important issue in women’s lives. The amount of bone that we gain during the teenage years significantly affects our bone density as we become older, especially during menopause and older age when bone fractures are most common. This raises the final and important question:

What do we know about Fracture Risk and the Use of Depo?

There are very few studies about Depo and fractures. We care about bone density because it provides an important clue about our risk for breaking bones. We know from Canadian population-based data (Canadian Multicentre Osteoporosis Study www.camos.org) that those people who lose bone more rapidly are at greater risk for fractures than those not losing bone or those not losing bone as quickly (21). This suggests that Depo, which causes early and fast bone loss, might increase the risk for fractures during this time of rapid bone loss. However, a recent study in Britain (using family doctor and medical records) followed over 300,000 women of all ages for an average of about five years to see if new fractures were more likely to happen in women who had used Depo than in women who had not used it (22). The researchers found that women who just started Depo had no change in their risk for new fractures (22). Because all women studied had medical records and the whole population of non-Depo using women had information about clinical factors related to fracture risk, this study could also assess the fracture risk in women before they started Depo. Women who later used Depo already had a significant, 28% greater risk for fracturing before they started Depo. This higher fracture risk was related to health problems, teen pregnancies and risky lifestyles.

In Summary

We have learned that the 12-week injection of high dose progestin in Depo-Provera® used for contraception makes our own estrogen levels (and usually our number of menstrual cycles) decrease. This causes rapid bone loss for about the first two years after starting Depo. However, bone loss then slows to normal even though Depo is continued. This bone response to Depo is similar in both teenagers and young adult women (20s through 40s). However, for both teens and older menstruating women, when Depo is stopped, rising estrogen levels with menstrual cycle recovery and persistent progestin (acting like progesterone to cause increased new bone formation) together cause an increase in bone density. There is usually recovery to a level of spinal bone density that is higher than before starting Depo and a slower but also complete recovery of hip bone density. The best and most important observation of all is that women’s risk for breaking bones does not increase just from using Depo. A higher fracture risk was seen in women who used Depo but this was because they tended to be disadvantaged medically and socially as well as having less healthy lifestyles. Despite the reassurances we are giving here, women on Depo should make efforts to ensure a healthy lifestyle and avoid behaviours that are risky for bone health: resources/abcs-osteoporosis-prevention-premenopausal-women.

References:

1. Davis A. Use of depot medroxyprogesterone acetate contraception in adolescents. The Journal of reproductive medicine. 1996;41(5 Suppl):407-13.

2. Clark MK, Sowers MR, Nichols S, Levy B. Bone mineral density changes over two years in first-time users of depot medroxyprogesterone acetate. Fertility and sterility. 2004;82(6):1580-6.

3. Lara-Torre E, Edwards CP, Perlman S, Hertweck SP. Bone mineral density in adolescent females using depot medroxyprogesterone acetate. Journal of pediatric and adolescent gynecology. 2004;17(1):17-21.

4. Lloyd T, Andon MB, Rollings N, Martel JK, Landis JR, Demers LM, et al. Calcium supplementation and bone mineral density in adolescent girls. Jama. 1993;270(7):841-4.

5. Cromer BA, Scholes D, Berenson A, Cundy T, Clark MK, Kaunitz AM. Depot medroxyprogesterone acetate and bone mineral density in adolescents—the Black Box Warning: a Position Paper of the Society for Adolescent Medicine. Journal of adolescent health. 2006;39(2):296-301.

6. Berger C, Goltzman D, Langsetmo L, Joseph L, Jackson S, Kreiger N, et al. Peak bone mass from longitudinal data: implications for the prevalence, pathophysiology, and diagnosis of osteoporosis. Journal of Bone and Mineral Research. 2010;25(9):1948-57.

7. Lee EY, Kim D, Kim KM, Kim KJ, Choi HS, Rhee Y, et al. Age-related bone mineral density patterns in Koreans (KNHANES IV). The Journal of Clinical Endocrinology & Metabolism. 2012;97(9):3310-8.

8. Krall EA, Dawson-Hughes B. Heritable and life-style determinants of bone mineral density. Journal of Bone and Mineral Research. 1993;8(1):1-9.

9. Vestergaard P, Rejnmark L, Mosekilde L. Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporosis international. 2006;17(6):807-16.

10. Petit MA, Prior JC, Barr SI. Running and ovulation positively change cancellous bone in premenopausal women. Medicine and science in sports and exercise. 1999;31(6):780-7.

11. Sowers M, Randolph JF, Crutchfield M, Jannausch ML, Shapiro B, Zhang B, et al. Urinary ovarian and gonadotropin hormone levels in premenopausal women with low bone mass. Journal of Bone and Mineral Research. 1998;13(7):1191-202.

12. Li D, Hitchcock CL, Barr SI, Yu T, Prior JC. Negative spinal bone mineral density changes and subclinical ovulatory disturbances—prospective data in healthy premenopausal women with regular menstrual cycles. Epidemiologic reviews. 2013:mxt012.

13. Cundy T, Ames R, Horne A, Clearwater J, Roberts H, Gamble G, et al. A randomized controlled trial of estrogen replacement therapy in long-term users of depot medroxyprogesterone acetate. The Journal of Clinical Endocrinology & Metabolism. 2003;88(1):78-81.

14. Albertazzi P, Bottazzi M, Steel SA. Bone mineral density and depot medroxyprogesterone acetate. Contraception. 2006;73(6):577-83.

15. Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Archives of pediatrics & adolescent medicine. 2005;159(2):139-44.

16. Harel Z, Johnson CC, Gold MA, Cromer B, Peterson E, Burkman R, et al. Recovery of bone mineral density in adolescents following the use of depot medroxyprogesterone acetate contraceptive injections. Contraception. 2010;81(4):281-91.

17. Paiva LC, Pinto-Neto AM, Faundes A. Bone density among long-term users of medroxyprogesterone acetate as a contraceptive. Contraception. 1998;58(6):351-5.

18. Kaunitz AM, Arias R, McClung M. Bone density recovery after depot medroxyprogesterone acetate injectable contraception use. Contraception. 2008;77(2):67-76.

19. Rosenberg L, Zhang Y, Constant D, Cooper D, Kalla AA, Micklesfield L, et al. Bone status after cessation of use of injectable progestin contraceptives. Contraception. 2007;76(6):425-31.

20. Berenson AB, Rahman M, Breitkopf CR, Bi LX. Effects of Depot Medroxyprogesterone Acetate and 20 μg Oral Contraceptives on Bone Mineral Density. Obstetrics and gynecology. 2008;112(4):788.

21. Berger C, Langsetmo L, Joseph L, Hanley DA, Davison KS, Josse RG, et al. Association between change in BMD and fragility fracture in women and men. Journal of Bone and Mineral Research. 2009;24(2):361-70.

22. Lanza LL, McQuay LJ, Rothman KJ, Bone HG, Kaunitz AM, Harel Z, et al. Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture. Obstetrics & Gynecology. 2013;121(3):593-600.

Type: 
Articles
Updated Date: 
April 14, 2015

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