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Clinical Reviews


Bone loss in young women

Whether it is depleted by GnRH agonists, athleticism, or glucocorticoids, swift intervention can often restore BMD

March 2006 · Vol. 18, No. 3

KEY POINTS

  • In young women, many cases of osteoporosis are caused by hypoestrogenism resulting from hormone treatment (eg, GnRH agonists, aromatase inhibitors) or lifestyle adaptations (elite athletics, eating disorders).
  • Treatment of osteoporosis in young women can often be successful with the use of estrogen or “androgenic” progestins.
  • Chronic glucocorticoid treatment is a common cause of clinically significant osteoporosis in young women. Glucocorticoid-induced osteoporosis is an important cause of premenopausal osteoporotic fractures.
  • ObGyns play a key role in ensuring that women enter midlife with strong bones. A focus on young women at very high risk for osteoporosis will help to ensure that our patients build their future bone health on a strong foundation.

ObGyns are very well trained to diagnose and treat women with osteoporosis, most of whom are perimenopausal and menopausal. We are also treating a significant number of young women at risk for osteoporosis because of lifestyle choices or medical treatment of endometriosis or rheumatic diseases. Treatment of this population poses unique challenges and requires specialized approaches.

An important caveat in any discussion of bone loss in young women: Few randomized clinical trials have assessed the efficacy of the various treatments available. In most treatment studies of osteoporosis in young women, bone mineral density (BMD)—an intermediate biometric endpoint—is the primary treatment outcome. In contrast, in the best studies in the menopausal population, the primary treatment outcome is bone fracture—a clinically important endpoint.

In addition, fewer consensus recommendations are available on the management of osteoporosis in young women than for its treatment in menopausal women. In this article, 3 different kinds of cases of bone loss in young women are used to develop key clinical points.

CASE 1 HISTORY

A teen with pelvic pain, bone loss

Therapy eased pain but decreased BMD

A 19-year-old woman has a 3-year history of severe, disabling dysmenorrhea. For 2 years she was treated with nonsteroidal anti-inflammatory drugs and cyclic estrogen-progestin contraceptives before switching to continuous oral contraceptives. These interventions did not relieve her pain. When she was 18, laparoscopy revealed stage I endometriosis, which was resected, providing 6 months of relief. When her pain recurred, the patient was started on leuprolide acetate depot, which caused amenorrhea and provided excellent pain relief. The patient said the leuprolide had “given back her life”. After 6 months of leuprolide therapy, a DXA bone scan demonstrated osteoporosis with a lumbar spine Z score of–2.6.

What treatment do you recommend?

Under age 25, use Z score, not T score

The diagnosis of osteoporosis in very young women is complex and continues to evolve. Physicians have been educated to use the T score (comparison to the mean peak bone mass of young adults) to assess BMD in menopausal women, in whom a decrease in T score of 1 standard deviation is associated with a 2- to 4-fold increase in fracture risk. However, teenage women are often still gaining bone mineral mass as the skeleton develops, so their T scores are normally below that of the peak bone mass of an adult woman. The Z score gives a good comparison of their bone mass with that of teens of the same sex at a similar developmental stage. Most experts agree that, when using DXA test results to assess bone density in women younger than 25, the Z score should be used.1 In one recent study, peak bone mass in the spine was achieved at approximately 23 years of age.2 As women reach age 25, the T and Z scores converge (FIGURE 1).

FIGURE 1 The Z score is more informative when the patient is under 25


The Z score compares the patient with persons of the same age and sex. The T score compares the patient with young normal adults of the same sex. Since bone mass increases until approximately age 20 to 25 years, it is best to use the Z score to evaluate the bone mineral density of women younger than 25 years.1 Reprinted from Gafni RI, Baron J. Overdiagnosis of osteoporosis in children due to misinterpretation of dual energy x-ray absorptiometry. J Pediatr. 2004;144:253–257. ©2004 with permission from Elsevier.

Treatment

For this patient with osteoporosis, there are several approaches to treatment:

Ensure adequate vitamin D and calcium. Vitamin D should be prescribed in doses of 400 to 800 IU daily. A recent meta-analysis reported that 800 IU vitamin D daily appears to provide better protection against osteoporotic fractures than 400 IU in menopausal women.3 Consider measuring 25-hydroxy vitamin D levels to assess the patient’s stores of this important pre-vitamin. Many young women are vitamin D-deficient.

Calcium intake should be in the range of 1,500 mg daily. To achieve this level of calcium intake, a calcium supplement, 500 to 1,000 mg daily, will probably need to be prescribed.

Discontinue leuprolide treatment. Typically, menses and ovarian estrogen production resume once leuprolide is stopped, and bone mass begins to recover. If pain recurs, the patient could be treated with cyclic or continuous estrogen-progestin contraceptives, depot-subQ Provera, a progestinreleasing intrauterine device, or a second laparoscopy procedure.

Continue leuprolide therapy and initiate steroid add-back treatment. Options shown to be effective in preserving bone mass in young women taking a gonadotropin-releasing hormone (GnRH) analogue include:

  • norethindrone acetate, 5 mg daily,
  • conjugated equine estrogen (Premarin), 0.3 or 0.625 mg daily, plus a progestin, and
  • low-dose transdermal estrogen, 25 μg daily, plus a progestin.

Key trials

Lupron Add-Back Study. Women with endometriosis and chronic pelvic pain were randomly assigned to 1 of 4 treatment groups:

  • leuprolide alone,
  • leuprolide plus an oral synthetic progestin, norethindrone acetate, 5 mg daily,
  • leuprolide plus “low-dose” conjugated equine estrogen, 0.625 mg, plus norethindrone acetate, 5 mg daily, or
  • leuprolide plus “high-dose” conjugated equine estrogen, 1.25 mg, plus norethindrone acetate, 5 mg daily.4

Women in all 4 groups received depotleuprolide, 3.75 mg intramuscularly every 4 weeks for 1 year. Over 1 year of treatment, BMD decreased significantly in the women who received the GnRH agonist alone. Bone density was preserved in the 3 groups that received steroid add-back.

Vasomotor symptoms were significantly reduced in all 3 groups receiving steroid add-back therapy, compared with the placebo group. However, more women in the group that received the larger dose of estrogen dropped out of the study than from the other groups because of more significant pelvic pain.

In summary, norethindrone, 5 mg daily, or low-dose conjugated equine estrogen, 0.625 mg, plus norethindrone acetate, 5 mg daily, were both effective steroid add-back regimens for prevention of bone loss in young women with endometriosis being treated with long-term GnRH analogues (TABLE 1).

GnRH analogue vs GnRH plus estradiolprogestin. In another trial, women who experienced endometriosis and pelvic pain were randomized to receive a GnRH agonist alone or a GnRH agonist plus low-dose transdermal estradiol, 25 μg daily, plus medroxyprogesterone acetate, 2.5 mg daily, for 6 months. Women in both groups had similar improvement in pelvic pain symptoms and a similar decrease in endometriosis surgical staging scores as determined by laparoscopy before and after treatment. However, the women who received the GnRH agonist alone, without add-back therapy, had more vasomotor symptoms and a greater decline in BMD than the women who received the GnRH agonist plus low-dose transdermal estradiol plus progestin.5

This study supports the estrogenthreshold hypothesis6 that there is a “sweet spot” in estradiol concentration where vasomotor symptoms and bone loss can be attenuated, but where endometriosis lesion activity is suppressed. This “sweet spot” appears to be at an estradiol concentration of about 30 pg/mL (FIGURE 2).

GnRH analogue vs GnRH plus teriparatide. A synthetic parathyroid analogue (PTH 1-34, teriparatide, Forteo) has been demonstrated to prevent bone loss in hypoestrogenic women. In this study, women with pelvic pain and endometriosis were randomized to treatment with a GnRH agonist alone or a GnRH agonist plus teriparatide for 6 months. Women receiving the GnRH agonist alone had a decrease in BMD at the spine of 3.5%, when measured in the lateral plane. Women receiving combined treatment had an increase in BMD at the spine of 3.4%.7

The Food and Drug Administration (FDA) has approved teriparatide at a dose of 20 μg daily by subcutaneous injection for the treatment of osteoporosis. A major advantage of PTH is that it appears to stimulate both osteoblasts and osteoclasts. In contrast, estrogen may preferentially block osteoclast activity without significantly stimulating osteoblasts. A major disadvantage of PTH: It is currently available only as a daily injection. It also is more expensive than estrogen or a synthetic progestin.

CASE 1 MANAGEMENT

A teen with pelvic pain, bone loss

Long-term combined therapy improved her BMD

This patient strongly preferred to continue the leuprolide treatment because it was so effective in treating her pelvic pain. She continued her leuprolide treatment and started norethindrone acetate 5 mg daily. She reported continued excellent control of her pelvic pain on the combined regimen of leuprolide plus norethindrone acetate. Follow-up bone density measurement demonstrated significant improvement. She continues on long-term combined therapy and is scheduled for annual BMD measurements.

CASE 2 HISTORY

The female athlete triad

A college-age dancer with an eating disorder

A 21-year-old elite ballet dancer, height 5’4” and weight 104 lb (BMI 17.8 kg/m2), presents with a history of a stress fracture of her foot. Besides being amenorrheic, she is on a high-fiber macrobiotic diet. DXA measurement demonstrates a Z score consistent with osteoporosis. She refuses to take estrogen-progestin contraceptives because she claims they impair her ability to train for her dance performances. She wonders if she should start alendronate therapy.

The female athlete triad is the combination of amenorrhea, disordered eating, and osteoporosis.8 In young female athletes, exercise and disordered eating may cause menstrual irregularity, and either disordered eating or menstrual irregularity, or both, may cause decreased BMD.9

Strenuous exercise has divergent effects on trabecular and cortical bone. By causing hypoestrogenism, strenuous exercise decreases bone density at cortical sites (vertebral spine). However, the weight-bearing exercise itself can lead to an increase in bone density at weight-bearing sites.10

Many elite athletes with the female athlete triad do not want to alter the intensity of their training or their diet, which might result in weight gain and resolution of the osteoporosis. Some elite athletes report that they do not want to take standard birth control pills because they believe the pill may impair their training and peak competitive performance. The clinician is often challenged by these strongly held beliefs to identify a treatment plan that will reverse the bone loss.

Is systemic disease involved? Occasionally, systemic disease causes or contributes to low bone mass in a young woman. Laboratory tests may help in screening some women for these diseases (TABLE 2).

FIGURE 2 Aim for the “sweet spot” in estradiol concentrations


According to the estrogen-threshold hypothesis, there is a range, or “sweet spot,” of estradiol concentrations where endometriosis lesion activity is suppressed and vasomotor symptoms and bone loss are not excessive. In humans, estrogen concentrations in the range of 30 pg/mL appear to be associated with decreased endometriosis pain and minimal degrees of bone loss. At estradiol levels of less than 10 pg/mL, bone loss is markedly accelerated.6 Reprinted from Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol. 1992;166:740–745. ©1992 with permission from Elsevier.TABLE 1

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