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.