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Short- and long-term impact of gonadotropin-releasing hormone analogue treatment on bone loss and fracture
Short- and long-term impact of gonadotropin-releasing hormone analogue treatment on bone loss and fracture May-Tal Sauerbrun-Cutler, M.D.a and Ruben Alvero, M.D.b a Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University and Women & Infants Hospital, Providence, Rhode Island; and b Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Stanford Medical School, Sunnyvale, California
Gonadotropin-releasing hormone analogues (GnRH-a) are commonly utilized in moderate to severe endometriosis to induce atrophy of endometriotic lesions. Unfortunately, cessation of therapy can lead to recurrence of symptoms. Therefore, long term therapy is sometimes necessary. GnRH analogues cause an immediate decrease in bone mineral density which usually recovers after cessation of its use. However, this recovery in bone mineral density may not always occur after long term use. In order to prevent the deleterious effects on bone, add-back therapy is used frequently. This review will explore the impact of GnRH analogues on both bone loss and fracture risk as well as describe different add-back regimens. (Fertil SterilÒ 2019;112:799–803. Ó2019 by American Society for Reproductive Medicine.) Key Words: Bone loss, add-back therapy, GnRH analogues, endometriosis Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/54056-29038
G
onadotropin-releasing hormone analogues (GnRH-a) are effective for the treatment of endometriosis, fibroids, adenomyosis, fertility preservation and precocious puberty. Of the various formulations that exist, the depo leuprolide acetate is most commonly used in the United States. This formulation is administered intramuscularly at a dose of 3.75 mg monthly or 11.25 mg every 3 months. Other depo formulations include goserelin acetate, a subcutaneous implant which is administered as a monthly 3.6 mg subcutaneous implant or a 3-month 10.8 mg implant. Nafarelin acetate, an intranasal spray, is administered at 200 mcg per pump with daily doses ranging from 400 to 1600 mcg (1).
GnRH analogues are extremely effective at reducing pelvic pain related to endometriosis by inhibiting gonadotropin release from the pituitary via receptor downregulation. Since the amino acid substitutions in the decapeptide reduce clearance and increase half-life, receptors are not restored to the cell surface and the gonadotrope eventually becomes desensitized. This action induces a hypoestrogenic state which leads to less painful symptoms by suppressing the endometriotic implants. Despite being effective for pain relief, they have undesirable hypoestrogenic side effects including vasomotor symptoms, reduction in bone mineral density (BMD), mood swings, and vaginal dryness.
Received September 25, 2019; accepted September 26, 2019. M.-T.S.-C. has nothing to disclose. R.A. has nothing to disclose. Correspondence: Ruben Alvero, M.D., Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Stanford Medical School, 1195 W Fremont Ave, Sunnyvale, CA 94087 (E-mail: [email protected]). Fertility and Sterility® Vol. 112, No. 5, November 2019 0015-0282/$36.00 Copyright ©2019 American Society for Reproductive Medicine, Published by Elsevier Inc. https://doi.org/10.1016/j.fertnstert.2019.09.037 VOL. 112 NO. 5 / NOVEMBER 2019
Bone is constantly undergoing resorption and bone formation and is highly susceptible to the hypoestrogenic effects of GnRH-a. Estrogens play an important role in bone turnover, inhibiting osteoclast activity which reduces bone resorption. Other sex steroids are reduced during GnRH-a treatment and compromise bone health. These include androgens which stimulate osteoblast activity and stimulate bone formation. Most progestins show neutral effects on bone except for norethindrone acetate (NETA) and tibolone which are protective and medroxyprogesterone acetate which induces bone loss (2). NETA is a progestin compound from the estrane family and is converted in the liver to ethinyl estradiol which is the likely mechanism for its estrogenic effects on bone. Tibolone is a synthetic steroid with weak estrogen, progesterone, and androgen activity and is approved for use in over 90 countries although not the United States or Canada.
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VIEWS AND REVIEWS The high prevalence of osteoporosis in post-menopausal women makes it critical to understand both the short and long-term effects of GnRH-a on bone health and fracture risk. Osteoporosis is common and can have severe health consequences with half of European white women sustaining a fracture by age 70 (3). Even if the short-term risks of GnRHa are minimal, a woman reaching menopause with a lower bone density induced by GnRH-a earlier in life will face a higher risk of osteoporosis and hip fracture and preserving BMD prior to menopause is critical. BMD, which is measured in g/cm2, is typically tested with the dual energy X-ray absorptiometry (DXA) scan although other serum or urine markers have been used to assess bone health such as deoxypyridinoline (DPD) and cross-linked Ntelopeptides. However, these markers are primarily used in research and are not used clinically to guide treatment for patients using GnRH-a. DPD is a cross-link for Type I collagen which accounts for over 90% of bone matrix. DPD is released when bone resorption takes place and can be measured in the urine unaffected by other factors such as diet. Telopeptides provide the terminal cross-links of the three collagen chains that constitute the bone matrix and are released and found in the urine with bone breakdown. While there may be a role for these urinary metabolites in assessing bone turnover, especially in women undergoing treatment to assess response, DXA remains the gold standard. Although there are no clear guidelines on when and how often to assess for bone loss in patients on GnRH-a, a DXA scan is recommended for patients on prolonged GnRH therapy or for those with risk factors for bone loss. Some of these risk factors include diabetes and chronic steroid use. It is also important to understand how to interpret this test in different age groups. Those caring for menopausal women are primarily concerned with the T-score measurement when diagnosing osteoporosis or osteopenia, which compares the measurement in the patient with a healthy young adult. In adolescent women, the Z-scores compares with age-matched peers and are thus more accurate for measurement (4). A Z-score of % 2.5 standard deviation is low, indicating a clinically significant low bone mass for age and gender. A Z-score between 1.0 and 2.5 standard deviation is intermediate and indicates that a patient may be at risk for low bone mass and that the medication likely should be stopped or addback initiated if not already started. The European Society for Human Reproduction and Embryology guideline expert opinion also recommends caution in the use of GnRH agonists in younger women who have not reached maximum bone density (5). Most of the literature on bone health and GnRH-a focuses on patients with endometriosis. However baseline bone density in patients with endometriosis has not been shown to be different than those with other diagnoses, allowing these data to be extrapolated to other populations using GnRH analogues (3).
ine fibroids and to correct anemia (6). The FDA also approves analogues for short-term use for treatment of endometriosis-related pelvic pain because the data shows lack of long-term harm. Prior to the widespread use of add-back therapy, some studies showed immediate bone density loss after 6 months of treatment of GnRH-a therapy. The peak bone loss ranges were from 2% to 6% (3, 7-9) from baseline. However, by a year after cessation, the BMD had partially to fully recovered. In some studies, with longer follow-up, there was still a decrease in bone mineral density. However, the rate of loss was less significant between 6 to 12 months. In a recent review, 156 women receiving leuprorelin for 6 months continued to show a significant loss in the BMD median percentage change from their pre-treatment values in both the total hip (-1.1%) and lumbar spine (-1.3%) a year after cessation (8). A similar study of 138 women taking leuprolide for 6 months continued to show a significant decrease in BMD median percentage change in both total hip (-1.3%) and lumbar spine (-1.7%) 12 months after cessation (9). This small percentage decrease from baseline after short term use may be statistically significant but it is unclear if it is clinically significant since the patients were unlikely to decrease their BMD into osteopenia or osteoporosis. A small number of studies with even longer term follow of up to two years after cessation of GnRH-a therapy showed that healthy women resolved their BMD back to baseline (10, 11). Although these studies are encouraging, they only evaluated lumbar spine bone mineral density and there is evidence that hip or proximal femur may not recover as quickly (3). Stevenson et al. (3) found that 6 months of treatment with goserelin alone produced a decrement in bone density of 4% in both the lumbar spine and the proximal femur. There was some recovery of bone density in the lumbar spine after stopping therapy, but there was no recovery seen in the proximal femur during the 6 months following cessation of treatment (3). However, in this study BMD was not followed beyond 6 months after cessation so it is possible that after a year it may have recovered. Not all GnRH-a will affect bone loss in the same way. When comparing leuprolide acetate to buserelin acetate nasal spray in 27 women with endometriosis or myomata, buserelin had less of an effect on bone mineral density. The subjects received drug therapy for 6 months and were subsequently followed for 1 year. Compared with the baseline value, the mean decrease in the buserelin group lumbar BMD was 3.7% at 6 months, 1.7% at 12 months, and 0.4% at 18 months. In the leuprolide group, lumbar BMD decreased respectively by 5.1%, 6.2%, and 4.3% (12).This difference may be attributed to milder suppression of serum sex hormone levels. Buserelin is not available in the United States.
IMPACT OF SHORT-TERM (6 MONTHS OR LESS) ON BONE LOSS AND FRACTURE
ADD-BACK THERAPY
Currently, the Food and Drug Administration (FDA) approves GnRH-a treatment in conjunction with iron administration for short-term presurgical treatment of uter800
Given the level of concern surrounding bone loss and menopausal side effects induced by GnRH-a, different types of add-back therapies have been trialed. The rationale behind add-back therapy is based on the threshold theory that lower VOL. 112 NO. 5 / NOVEMBER 2019
Fertility and Sterility®
TABLE 1 Add-back regimens. Duration (mo)
Regimen E2 patch .025 mg MPA 5 mg/d MPA 100 mg/d NETA 5 mg/d CEE 0.625 mg/d NETA 5 mg/d CEE 1.25 mg/d NETA 5 mg/d E2 2 mg/d NETA 1 mg/d E2 2 mg/d NETA 1 mg/d CEE 0.625 mg/d NETA 5 mg/d E2 1 mg/d NETA .5 mg/d E2 valerate 1 mg/d MPA 2.5 mg/d
Bone loss
Article
6
Y
Edmonds 1994 (30)
6 12 12
N N N
Ma€k€ar€ainen 1996 (31) Hornstein 1998 (14) Hornstein 1998 (14)
12
N
Hornstein 1998 (14)
6-24
Y
Pierce 2000 (24)
6
N
Cheung 2005 (32)
12
N
6
Y
Divasta 2015 (17) Hornstein 1998 (14) Lee 2016 (33)
6
Y
Tsai 2016 (34)
Note: CEE ¼ conjugated equine estrogens; E2 ¼ micronized 17 beta estradiol; NETA ¼ norethindrone acetate; MPA ¼ medroxyprogesterone acetate. Sauerbrun-Cutler. Sauerbrun-Cutler. Impact of GnRH analog treatment.. Fertil Steril 2019.
levels of estrogen are needed to protect bone and decrease menopausal symptoms than to activate endometriosis tissue (13). If estrogen levels remain below 50 pg/ml with addback regimens, bone loss is prevented, and ectopic implants are not stimulated (14). There are many combinations of add-back regimens that are effective in preventing bone loss when administered with GnRH agonists. These addback regimens include progestin monotherapy such as norethisterone/norethindrone acetate (NETA), estrogen-progestin combinations, selective estrogen receptor modulators such as raloxifene, bisphosphonates, tibolone, and testosterone. Combined oral contraceptives should not be used as addback therapy given their supra-physiologic hormone levels. After a randomized control trial (RCT) (14) showed that daily dosing of 5 mg of NETA was effective at preventing bone loss, the FDA approved this medication as add-back therapy for co-administration with GnRH analogues for patients with endometriosis. This RCT evaluated 200 patients enrolled in the initial trial and 123 patients completed at least 280 days of therapy. Patients were treated for 52 weeks with a 3.75 mg dose monthly of leuprolide acetate. There were 3 different add-back regimens and 1 placebo group: A, daily placebo; B, daily norethindrone acetate, 5 mg; C, daily norethindrone acetate, 5 mg and conjugated equine estrogens, 0.625 mg; and D, daily norethindrone acetate, 5 mg and conjugated equine estrogens (CEE), 1.25 mg. All addback groups had mean BMD at or above their baseline both after completion of therapy and 2 years after cessation of GnRH-a therapy. In contrast, the placebo group had a loss in bone density which reversed slowly and had not returned to baseline at the final follow-up visit. Group D with the highest level of estrogen had a quicker return to dysmenorrhea and pelvic tenderness than the other groups. Therefore, high daily doses of CEE (1.25 mg) should be used with caution due to the earlier return of pain symptoms. Given the equivalence of the VOL. 112 NO. 5 / NOVEMBER 2019
NETA alone compared to the NETA plus low dose conjugated estrogen, both can be administered safely as add-back therapy. Many other trials and meta-analyses have shown different add-back therapies are equivalent and that BMD is preserved throughout the GnRH-a administration (15). The add-back regimens studied are listed in Table 1. The regimens with low dose norethindrone or those that used low dose medroxyprogesterone acetate without estrogen were not enough to prevent bone loss and should be avoided. There was initial concern with add-back therapy and its ability to preserve bone density in adolescents when a retrospective study showed that one third of subjects exhibited skeletal deficits at the spine (Z score less than -1) after an average length of GnRH-a treatment of 11 months (16). However, a RCT of 65 young women ages 15 to 22 years revealed that add-back therapy either with 5 mg of NETA or 5 mg NETA plus 0.625 mg CEE was equally effective at preventing bone loss in adolescents throughout the one year treatment period of a GnRH agonist (17). The norethindrone acetate plus CEE group had a significant increase in BMD over time in comparison to the norethindrone acetate group. Lean mass increased and quality-of-life was also greater in the CEE þ NETA group. Therefore, in younger patients combining NETA with estrogen as add-back therapy may be beneficial. In addition, vitamin D and calcium supplements should be taken concurrently. The timing of initiation of add-back therapy is also important. There is no reason to defer treatment of addback therapy. Side effects of add-back therapy are minimal and may include spotting, bloating, and breast tenderness (1). In addition, most women report improvement in quality of life and vasomotor symptoms once initiating add-back therapy. The American Society for Reproductive Medicine and the European Society for Human Reproduction and Embryology both recommend starting the add-back therapy at the same time as the GnRH-agonist treatment for patients with endometriosis related pelvic pain (18, 19). Unfortunately, despite these evidence-based recommendations, one third of women defer the start of add-back therapy as evidenced by a retrospective analysis of a large pharmacy claims database (20). The timing of add-back therapy for women with myomas may be different than those with endometriosis. Studies have shown that sequential treatment such as starting after 6 months of therapy may provide better efficacy for fibroid symptom treatment than simultaneous treatment (21). Furthermore, if it is started too early, then it may stimulate myoma regrowth (22).
LONG-TERM TREATMENT: 12 OR MORE MONTHS There are limited data on long-term effects of GnRH-a therapy on bone health. Leuprolide administered for several years with add-back therapy has been utilized in patients with recurrent pain with a few case series reporting encouraging results. A pilot study enrolled 5 patients with severe pelvic pain and laparoscopically confirmed endometriosis who 801
VIEWS AND REVIEWS were treated for GnRH analogues for 10 years with 1 mg daily oral estradiol and 0.35 mg norethindrone every 2 days. BMD testing was performed annually for 10 years and remained stable (23). Another RCT with up to two years of GnRH-a treatment showed contradictory results. This small RCT of 49 patients showed decreased BMD from baseline at 6 years after treatment. However, this study used a low progestin dose as add-back therapy (1 mg/daily NETA) with 2mg estradiol which may not have been sufficient to prevent bone loss (24).
FRACTURE RISK There are few long-term observational studies evaluating fracture risk after GnRH-a treatment. Hypothetical models have been developed to estimate the 10-year major osteoporosis related fracture risk later in life. These models used the Fracture Risk Assessment (FRAX) tool and the trabecular bone score along with assumptions from prior studies of a 6 month decline in BMD from 2% to 6% to model the risk of osteoporotic fracture by age 75. The modeling showed that women with a baseline BMD less than the 25th percentile who have a 4 percent or more reduction in BMD will likely need to initiate medical treatment for osteoporosis later in life that they would have otherwise not required (25, 26). These models are not perfect because they assume that bone loss does not recover following discontinuation of treatment. Nevertheless, with add-back therapy co-administration, limited recovery should not be assumed. Once improved, these models may aid in counseling patients about their future risk of osteoporosis. Other small observational studies have shown that vitamin D receptor (VDR) gene polymorphisms as well as pretreatment deoxypyridinoline (DPD) levels can predict which patients will suffer from bone loss (27). Urinary DPD is used as a marker of bone resorption and is measured by highperformance chromatography. DPD is a breakdown product of type I fibrillar collagen and it occurs mainly in Type I collagen of bone. DPD levels show a high specificity for bone resorption (28). Forty-three patients who received GnRH-a for 6 months who had greater than two polymorphisms in the FokI or TaqI region of the VDR gene were more likely to show BMD reduction at 6 months after the start of GnRH-a therapy (27) than patients with 2 or fewer polymorphisms. Urinary DPD levels were also used to predict bone loss. Fifty patients with endometriosis were treated with GnRH-a for 6 months and divided into a low BMD group and high BMD based on the median of percentage change in BMD at 12 months post treatment. The patients in the low BMD group had lower pretreatment levels of DPD than the high BMD group indicating that pretreatment DPD level may be predictive of higher GnRH-a induced bone damage (28). These studies still need to be replicated prior to clinical use. In the future they may be used to identify which patients are poor candidates for GnRH-a long term treatment (29).
data are few, add-back therapy may minimize long term bone loss in patients using GnRH-a for extended durations, especially for certain populations at higher risk of permanent bone loss. GnRH-a treatment duration should be minimized as much as possible in adolescents because they are at the peak of their bone formation and particularly susceptible to bone resorption. Add-back therapy should be used concurrently with GnRH-a and there should be no delay in starting the add-back with the start of suppression although delaying add-back start may be appropriate in patients with leiomyoma. While several protocols are effective (Table 1), the most common include either a high dose of NETA (5 mg/ day) with low-dose of CEE or norethindrone acetate (5 mg/ day) alone, which is the FDA approved choice. Calcium and vitamin D are recommended for all patients at risk of bone loss and should be encouraged in patients taking GnRH-a. BMD by the gold standard DXA test should be considered especially after more than 1 year on GnRH-a. In addition, a baseline bone density should be performed if there are any risk factors for osteoporosis. Add-back therapy when using long-term GnRH-a is effective and provides long-term hope for good quality of life in patients requiring this treatment regimen.
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CONCLUSION Short-term GnRH-a treatments combined with add-back therapy is unlikely to cause long term bone loss. Although 802
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Gonadotropin-releasing hormone analogues (GnRH-a) are commonly utilized in moderate to severe endometriosis to induce atrophy of endometriotic lesions. Unfortunately, cessation of therapy can lead to recurrence of symptoms. Therefore, long term therapy is sometimes necessary. GnRH analogues cause an immediate decrease in bone mineral density which usually recovers after cessation of its use. However, this recovery in bone mineral density may not always occur after long term use. In order to prevent the deleterious effects on bone, add-back therapy is used frequently. This review will explore the impact of GnRH analogues on both bone loss and fracture risk as well as describe different add-back regimens. (Fertil SterilÒ 2019;112:799–803. Ó2019 by American Society for Reproductive Medicine.) Key Words: Bone loss, add-back therapy, GnRH analogues, endometriosis Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/54056-29038
G
onadotropin-releasing hormone analogues (GnRH-a) are effective for the treatment of endometriosis, fibroids, adenomyosis, fertility preservation and precocious puberty. Of the various formulations that exist, the depo leuprolide acetate is most commonly used in the United States. This formulation is administered intramuscularly at a dose of 3.75 mg monthly or 11.25 mg every 3 months. Other depo formulations include goserelin acetate, a subcutaneous implant which is administered as a monthly 3.6 mg subcutaneous implant or a 3-month 10.8 mg implant. Nafarelin acetate, an intranasal spray, is administered at 200 mcg per pump with daily doses ranging from 400 to 1600 mcg (1).
GnRH analogues are extremely effective at reducing pelvic pain related to endometriosis by inhibiting gonadotropin release from the pituitary via receptor downregulation. Since the amino acid substitutions in the decapeptide reduce clearance and increase half-life, receptors are not restored to the cell surface and the gonadotrope eventually becomes desensitized. This action induces a hypoestrogenic state which leads to less painful symptoms by suppressing the endometriotic implants. Despite being effective for pain relief, they have undesirable hypoestrogenic side effects including vasomotor symptoms, reduction in bone mineral density (BMD), mood swings, and vaginal dryness.
Received September 25, 2019; accepted September 26, 2019. M.-T.S.-C. has nothing to disclose. R.A. has nothing to disclose. Correspondence: Ruben Alvero, M.D., Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Stanford Medical School, 1195 W Fremont Ave, Sunnyvale, CA 94087 (E-mail: [email protected]). Fertility and Sterility® Vol. 112, No. 5, November 2019 0015-0282/$36.00 Copyright ©2019 American Society for Reproductive Medicine, Published by Elsevier Inc. https://doi.org/10.1016/j.fertnstert.2019.09.037 VOL. 112 NO. 5 / NOVEMBER 2019
Bone is constantly undergoing resorption and bone formation and is highly susceptible to the hypoestrogenic effects of GnRH-a. Estrogens play an important role in bone turnover, inhibiting osteoclast activity which reduces bone resorption. Other sex steroids are reduced during GnRH-a treatment and compromise bone health. These include androgens which stimulate osteoblast activity and stimulate bone formation. Most progestins show neutral effects on bone except for norethindrone acetate (NETA) and tibolone which are protective and medroxyprogesterone acetate which induces bone loss (2). NETA is a progestin compound from the estrane family and is converted in the liver to ethinyl estradiol which is the likely mechanism for its estrogenic effects on bone. Tibolone is a synthetic steroid with weak estrogen, progesterone, and androgen activity and is approved for use in over 90 countries although not the United States or Canada.
799
VIEWS AND REVIEWS The high prevalence of osteoporosis in post-menopausal women makes it critical to understand both the short and long-term effects of GnRH-a on bone health and fracture risk. Osteoporosis is common and can have severe health consequences with half of European white women sustaining a fracture by age 70 (3). Even if the short-term risks of GnRHa are minimal, a woman reaching menopause with a lower bone density induced by GnRH-a earlier in life will face a higher risk of osteoporosis and hip fracture and preserving BMD prior to menopause is critical. BMD, which is measured in g/cm2, is typically tested with the dual energy X-ray absorptiometry (DXA) scan although other serum or urine markers have been used to assess bone health such as deoxypyridinoline (DPD) and cross-linked Ntelopeptides. However, these markers are primarily used in research and are not used clinically to guide treatment for patients using GnRH-a. DPD is a cross-link for Type I collagen which accounts for over 90% of bone matrix. DPD is released when bone resorption takes place and can be measured in the urine unaffected by other factors such as diet. Telopeptides provide the terminal cross-links of the three collagen chains that constitute the bone matrix and are released and found in the urine with bone breakdown. While there may be a role for these urinary metabolites in assessing bone turnover, especially in women undergoing treatment to assess response, DXA remains the gold standard. Although there are no clear guidelines on when and how often to assess for bone loss in patients on GnRH-a, a DXA scan is recommended for patients on prolonged GnRH therapy or for those with risk factors for bone loss. Some of these risk factors include diabetes and chronic steroid use. It is also important to understand how to interpret this test in different age groups. Those caring for menopausal women are primarily concerned with the T-score measurement when diagnosing osteoporosis or osteopenia, which compares the measurement in the patient with a healthy young adult. In adolescent women, the Z-scores compares with age-matched peers and are thus more accurate for measurement (4). A Z-score of % 2.5 standard deviation is low, indicating a clinically significant low bone mass for age and gender. A Z-score between 1.0 and 2.5 standard deviation is intermediate and indicates that a patient may be at risk for low bone mass and that the medication likely should be stopped or addback initiated if not already started. The European Society for Human Reproduction and Embryology guideline expert opinion also recommends caution in the use of GnRH agonists in younger women who have not reached maximum bone density (5). Most of the literature on bone health and GnRH-a focuses on patients with endometriosis. However baseline bone density in patients with endometriosis has not been shown to be different than those with other diagnoses, allowing these data to be extrapolated to other populations using GnRH analogues (3).
ine fibroids and to correct anemia (6). The FDA also approves analogues for short-term use for treatment of endometriosis-related pelvic pain because the data shows lack of long-term harm. Prior to the widespread use of add-back therapy, some studies showed immediate bone density loss after 6 months of treatment of GnRH-a therapy. The peak bone loss ranges were from 2% to 6% (3, 7-9) from baseline. However, by a year after cessation, the BMD had partially to fully recovered. In some studies, with longer follow-up, there was still a decrease in bone mineral density. However, the rate of loss was less significant between 6 to 12 months. In a recent review, 156 women receiving leuprorelin for 6 months continued to show a significant loss in the BMD median percentage change from their pre-treatment values in both the total hip (-1.1%) and lumbar spine (-1.3%) a year after cessation (8). A similar study of 138 women taking leuprolide for 6 months continued to show a significant decrease in BMD median percentage change in both total hip (-1.3%) and lumbar spine (-1.7%) 12 months after cessation (9). This small percentage decrease from baseline after short term use may be statistically significant but it is unclear if it is clinically significant since the patients were unlikely to decrease their BMD into osteopenia or osteoporosis. A small number of studies with even longer term follow of up to two years after cessation of GnRH-a therapy showed that healthy women resolved their BMD back to baseline (10, 11). Although these studies are encouraging, they only evaluated lumbar spine bone mineral density and there is evidence that hip or proximal femur may not recover as quickly (3). Stevenson et al. (3) found that 6 months of treatment with goserelin alone produced a decrement in bone density of 4% in both the lumbar spine and the proximal femur. There was some recovery of bone density in the lumbar spine after stopping therapy, but there was no recovery seen in the proximal femur during the 6 months following cessation of treatment (3). However, in this study BMD was not followed beyond 6 months after cessation so it is possible that after a year it may have recovered. Not all GnRH-a will affect bone loss in the same way. When comparing leuprolide acetate to buserelin acetate nasal spray in 27 women with endometriosis or myomata, buserelin had less of an effect on bone mineral density. The subjects received drug therapy for 6 months and were subsequently followed for 1 year. Compared with the baseline value, the mean decrease in the buserelin group lumbar BMD was 3.7% at 6 months, 1.7% at 12 months, and 0.4% at 18 months. In the leuprolide group, lumbar BMD decreased respectively by 5.1%, 6.2%, and 4.3% (12).This difference may be attributed to milder suppression of serum sex hormone levels. Buserelin is not available in the United States.
IMPACT OF SHORT-TERM (6 MONTHS OR LESS) ON BONE LOSS AND FRACTURE
ADD-BACK THERAPY
Currently, the Food and Drug Administration (FDA) approves GnRH-a treatment in conjunction with iron administration for short-term presurgical treatment of uter800
Given the level of concern surrounding bone loss and menopausal side effects induced by GnRH-a, different types of add-back therapies have been trialed. The rationale behind add-back therapy is based on the threshold theory that lower VOL. 112 NO. 5 / NOVEMBER 2019
Fertility and Sterility®
TABLE 1 Add-back regimens. Duration (mo)
Regimen E2 patch .025 mg MPA 5 mg/d MPA 100 mg/d NETA 5 mg/d CEE 0.625 mg/d NETA 5 mg/d CEE 1.25 mg/d NETA 5 mg/d E2 2 mg/d NETA 1 mg/d E2 2 mg/d NETA 1 mg/d CEE 0.625 mg/d NETA 5 mg/d E2 1 mg/d NETA .5 mg/d E2 valerate 1 mg/d MPA 2.5 mg/d
Bone loss
Article
6
Y
Edmonds 1994 (30)
6 12 12
N N N
Ma€k€ar€ainen 1996 (31) Hornstein 1998 (14) Hornstein 1998 (14)
12
N
Hornstein 1998 (14)
6-24
Y
Pierce 2000 (24)
6
N
Cheung 2005 (32)
12
N
6
Y
Divasta 2015 (17) Hornstein 1998 (14) Lee 2016 (33)
6
Y
Tsai 2016 (34)
Note: CEE ¼ conjugated equine estrogens; E2 ¼ micronized 17 beta estradiol; NETA ¼ norethindrone acetate; MPA ¼ medroxyprogesterone acetate. Sauerbrun-Cutler. Sauerbrun-Cutler. Impact of GnRH analog treatment.. Fertil Steril 2019.
levels of estrogen are needed to protect bone and decrease menopausal symptoms than to activate endometriosis tissue (13). If estrogen levels remain below 50 pg/ml with addback regimens, bone loss is prevented, and ectopic implants are not stimulated (14). There are many combinations of add-back regimens that are effective in preventing bone loss when administered with GnRH agonists. These addback regimens include progestin monotherapy such as norethisterone/norethindrone acetate (NETA), estrogen-progestin combinations, selective estrogen receptor modulators such as raloxifene, bisphosphonates, tibolone, and testosterone. Combined oral contraceptives should not be used as addback therapy given their supra-physiologic hormone levels. After a randomized control trial (RCT) (14) showed that daily dosing of 5 mg of NETA was effective at preventing bone loss, the FDA approved this medication as add-back therapy for co-administration with GnRH analogues for patients with endometriosis. This RCT evaluated 200 patients enrolled in the initial trial and 123 patients completed at least 280 days of therapy. Patients were treated for 52 weeks with a 3.75 mg dose monthly of leuprolide acetate. There were 3 different add-back regimens and 1 placebo group: A, daily placebo; B, daily norethindrone acetate, 5 mg; C, daily norethindrone acetate, 5 mg and conjugated equine estrogens, 0.625 mg; and D, daily norethindrone acetate, 5 mg and conjugated equine estrogens (CEE), 1.25 mg. All addback groups had mean BMD at or above their baseline both after completion of therapy and 2 years after cessation of GnRH-a therapy. In contrast, the placebo group had a loss in bone density which reversed slowly and had not returned to baseline at the final follow-up visit. Group D with the highest level of estrogen had a quicker return to dysmenorrhea and pelvic tenderness than the other groups. Therefore, high daily doses of CEE (1.25 mg) should be used with caution due to the earlier return of pain symptoms. Given the equivalence of the VOL. 112 NO. 5 / NOVEMBER 2019
NETA alone compared to the NETA plus low dose conjugated estrogen, both can be administered safely as add-back therapy. Many other trials and meta-analyses have shown different add-back therapies are equivalent and that BMD is preserved throughout the GnRH-a administration (15). The add-back regimens studied are listed in Table 1. The regimens with low dose norethindrone or those that used low dose medroxyprogesterone acetate without estrogen were not enough to prevent bone loss and should be avoided. There was initial concern with add-back therapy and its ability to preserve bone density in adolescents when a retrospective study showed that one third of subjects exhibited skeletal deficits at the spine (Z score less than -1) after an average length of GnRH-a treatment of 11 months (16). However, a RCT of 65 young women ages 15 to 22 years revealed that add-back therapy either with 5 mg of NETA or 5 mg NETA plus 0.625 mg CEE was equally effective at preventing bone loss in adolescents throughout the one year treatment period of a GnRH agonist (17). The norethindrone acetate plus CEE group had a significant increase in BMD over time in comparison to the norethindrone acetate group. Lean mass increased and quality-of-life was also greater in the CEE þ NETA group. Therefore, in younger patients combining NETA with estrogen as add-back therapy may be beneficial. In addition, vitamin D and calcium supplements should be taken concurrently. The timing of initiation of add-back therapy is also important. There is no reason to defer treatment of addback therapy. Side effects of add-back therapy are minimal and may include spotting, bloating, and breast tenderness (1). In addition, most women report improvement in quality of life and vasomotor symptoms once initiating add-back therapy. The American Society for Reproductive Medicine and the European Society for Human Reproduction and Embryology both recommend starting the add-back therapy at the same time as the GnRH-agonist treatment for patients with endometriosis related pelvic pain (18, 19). Unfortunately, despite these evidence-based recommendations, one third of women defer the start of add-back therapy as evidenced by a retrospective analysis of a large pharmacy claims database (20). The timing of add-back therapy for women with myomas may be different than those with endometriosis. Studies have shown that sequential treatment such as starting after 6 months of therapy may provide better efficacy for fibroid symptom treatment than simultaneous treatment (21). Furthermore, if it is started too early, then it may stimulate myoma regrowth (22).
LONG-TERM TREATMENT: 12 OR MORE MONTHS There are limited data on long-term effects of GnRH-a therapy on bone health. Leuprolide administered for several years with add-back therapy has been utilized in patients with recurrent pain with a few case series reporting encouraging results. A pilot study enrolled 5 patients with severe pelvic pain and laparoscopically confirmed endometriosis who 801
VIEWS AND REVIEWS were treated for GnRH analogues for 10 years with 1 mg daily oral estradiol and 0.35 mg norethindrone every 2 days. BMD testing was performed annually for 10 years and remained stable (23). Another RCT with up to two years of GnRH-a treatment showed contradictory results. This small RCT of 49 patients showed decreased BMD from baseline at 6 years after treatment. However, this study used a low progestin dose as add-back therapy (1 mg/daily NETA) with 2mg estradiol which may not have been sufficient to prevent bone loss (24).
FRACTURE RISK There are few long-term observational studies evaluating fracture risk after GnRH-a treatment. Hypothetical models have been developed to estimate the 10-year major osteoporosis related fracture risk later in life. These models used the Fracture Risk Assessment (FRAX) tool and the trabecular bone score along with assumptions from prior studies of a 6 month decline in BMD from 2% to 6% to model the risk of osteoporotic fracture by age 75. The modeling showed that women with a baseline BMD less than the 25th percentile who have a 4 percent or more reduction in BMD will likely need to initiate medical treatment for osteoporosis later in life that they would have otherwise not required (25, 26). These models are not perfect because they assume that bone loss does not recover following discontinuation of treatment. Nevertheless, with add-back therapy co-administration, limited recovery should not be assumed. Once improved, these models may aid in counseling patients about their future risk of osteoporosis. Other small observational studies have shown that vitamin D receptor (VDR) gene polymorphisms as well as pretreatment deoxypyridinoline (DPD) levels can predict which patients will suffer from bone loss (27). Urinary DPD is used as a marker of bone resorption and is measured by highperformance chromatography. DPD is a breakdown product of type I fibrillar collagen and it occurs mainly in Type I collagen of bone. DPD levels show a high specificity for bone resorption (28). Forty-three patients who received GnRH-a for 6 months who had greater than two polymorphisms in the FokI or TaqI region of the VDR gene were more likely to show BMD reduction at 6 months after the start of GnRH-a therapy (27) than patients with 2 or fewer polymorphisms. Urinary DPD levels were also used to predict bone loss. Fifty patients with endometriosis were treated with GnRH-a for 6 months and divided into a low BMD group and high BMD based on the median of percentage change in BMD at 12 months post treatment. The patients in the low BMD group had lower pretreatment levels of DPD than the high BMD group indicating that pretreatment DPD level may be predictive of higher GnRH-a induced bone damage (28). These studies still need to be replicated prior to clinical use. In the future they may be used to identify which patients are poor candidates for GnRH-a long term treatment (29).
data are few, add-back therapy may minimize long term bone loss in patients using GnRH-a for extended durations, especially for certain populations at higher risk of permanent bone loss. GnRH-a treatment duration should be minimized as much as possible in adolescents because they are at the peak of their bone formation and particularly susceptible to bone resorption. Add-back therapy should be used concurrently with GnRH-a and there should be no delay in starting the add-back with the start of suppression although delaying add-back start may be appropriate in patients with leiomyoma. While several protocols are effective (Table 1), the most common include either a high dose of NETA (5 mg/ day) with low-dose of CEE or norethindrone acetate (5 mg/ day) alone, which is the FDA approved choice. Calcium and vitamin D are recommended for all patients at risk of bone loss and should be encouraged in patients taking GnRH-a. BMD by the gold standard DXA test should be considered especially after more than 1 year on GnRH-a. In addition, a baseline bone density should be performed if there are any risk factors for osteoporosis. Add-back therapy when using long-term GnRH-a is effective and provides long-term hope for good quality of life in patients requiring this treatment regimen.
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CONCLUSION Short-term GnRH-a treatments combined with add-back therapy is unlikely to cause long term bone loss. Although 802
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