Bone and Depo-Provera
By Leon Speroff, MD
Clinicians are concerned that the contraceptive use of Depo-Provera is associated with the loss of bone. This is attributed to the fact that blood levels of estrogen with Depo-Provera are relatively lower over a period of time compared with a normal menstrual cycle. Indeed, lumbar and hip bone loss has been documented in cross-sectional studies.1,2 The first study was relatively small (30 women), but the second, both in New Zealand, involved 200 women. This bone loss has also been observed in women receiving a high oral dose of medroxyprogesterone acetate, 50 mg daily, a dose that suppresses LH, resulting in low estrogen levels.3 Another study documented decreased bone density, enhanced by lower body weight and duration of amenorrhea.4 A cross-sectional study in Brazil detected a loss of bone in the distal forearm (where trabecular bone predominates), but no effect of duration of use.5 An American cross-sectional study indicated a greater bone loss with increasing duration of use, especially in younger women, 18-21 years old.6
The degree of bone loss in the above studies is not as severe as that observed in the early postmenopausal years. Furthermore, this amount of bone loss is not so great that it cannot be regained. Bone density measurements in women who stopped using Depo-Provera indicated that the loss was regained in the lumbar spine but not in the femoral neck within two years even after long-term use.7 Most important, a cross-sectional study of postmenopausal women from these same investigators in New Zealand could not detect a difference in bone density comparing former users of Depo-Provera to never-users, indicating that any loss of bone during use is regained.8
A definitive response to this clinical concern is not possible because not all studies are in agreement. A cross-sectional study and two studies making comparisons with IUD and Norplant users in Thailand found no bone loss in long-term (greater than 3 years) users of Depo-Provera.9-11 And most important, longitudinal, prospective studies of bone fail to document bone loss in users of Depo-Provera. In Thailand, loss of forearm bone density could not be detected over three years of Depo-Provera use, suggesting that previous adverse findings could be explained by inadequate control of factors that affect bone, such as smoking and alcohol intake.10 A small prospective study documented stable forearm bone density over a six-month period.12 And a cross-sectional study in England could not detect a decrease in the bone density of the lumbar spine or the femoral neck despite relatively low estradiol levels in amenorrheic women who had been receiving depot medroxyprogesterone acetate for one to 16 years.13
Bone density increases rapidly and significantly during adolescence. Almost all of the bone mass in the hip and the vertebral bodies will be accumulated in young women by age 18, and the years immediately following menarche are especially important.14,15 For this reason any drug that prevents this increase in bone density may increase the risk of osteoporosis later in life. A prospective study in 47 adolescents documented that Depo-Provera (15 users) was associated with a loss of lumbar bone density (approximately 1.5% in one year) compared with the normal increases observed in users of Norplant (7 users) and oral contraceptives (9 users).16 Do adolescents who use Depo-Provera regain bone density after discontinuing this method of contraception, or are adolescents at greater risk for osteoporosis compared with women who use Depo-Provera later in life?
An example of bone loss that is regained is the bone loss associated with lactation. Secretion of calcium into the milk of lactating women approximately doubles the daily loss of calcium.17 In women who breastfeed for six months or more, this is accompanied by significant bone loss even in the presence of a high calcium intake.18 However, bone density rapidly returns to baseline levels in the six months after weaning.19 The bone loss is due to increased bone resorption, probably secondary to the relatively low estrogen levels associated with lactation. Calcium supplementation has no effect on the calcium content of breast milk or on bone loss in lactating women who have normal diets.20 Thus, studies indicate that any loss of calcium and bone associated with lactation is rapidly restored and therefore there is no effect on the risk of postmenopausal osteoporosis.21, 22
The mixed results, the degree of bone loss, some evidence the bone loss is regained, and the similarity to the benign bone loss associated with lactation all argue that the use of Depo-Provera should not be limited by this concern, and that supplemental estrogen treatment is not indicated (and would influence and complicate compliance). This concern will require ongoing surveillance of past users, and the results of a prospective multicenter assessment of this problem should be available in 2003. However, at the present time, in my view, this should not be a reason to avoid this method of contraception. I don’t believe that it is likely that bone loss occurs sufficiently to raise the risk of osteoporosis later in life.
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