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Hormone therapy and fractures [VMS] in postmenopausal women
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Oct 2022
Methods:
A prospective study of 1765 (1350 WLWH and 415 HIV−) postmenopausal Women's Interagency HIV Study (WIHS) participants was performed, including self-reported hormone therapy, use and fracture data from 2003 to 2017. Proportional hazard models determined predictors of new fractures at any site or at typical fragility fracture sites (hip, spine, wrist).
Concerns related to adverse cardiovascular outcomes highlighted by the Women's Health Initiative (WHI) studies in 2002 [25,26,33] led to declining hormone therapy use among women in the United States. However, subsequent analyses of the WHI found that risk of cardiovascular events depended on the timing of hormone exposure: no excess risk was observed in women under 60 years of age who were less than 10 years postmenopause [34,35]. Among women without HIV, mortality rates were actually lower in younger postmenopausal women on hormone therapy vs. hormone therapy nonusers. As a result, the North American Menopause Society (NAMS), the Endocrine Society, and the International Menopause Society have determined that benefits of hormone therapy may outweigh risks for certain populations of women, depending on age, onset of menopause, duration of hormone therapy, and comorbid conditions [16-18]. Despite these published guidelines and the availability of safer transdermal formulations of estrogen, hormone therapy use remains low among perimenopausal and postmenopausal women under age 60 years.
Vasomotor symptoms and hormone therapy use
At the index visit, fewer postmenopausal WLWH than women without HIV reported having VMS at least one time per day for the 2 weeks prior to their last visit (17% vs. 26%, P < 0.0001). At the index visit, 8% of postmenopausal WLWH and 4% of women without HIV reported hormone therapy use (P = 0.007). Among those who used hormone therapy, the following indications were reported: menopausal symptoms or VMS (50%), posthysterectomy (19%), osteoporosis prevention or treatment (7%), cardiovascular and neuropsychiatric reasons (1%), and other/nonidentified (22%). Over the 14-year observation period, the proportion of postmenopausal women reporting hormone therapy steadily decreased. In 2003, 19% and 15% (P = 0.37) of postmenopausal with and without HIV, respectively, reported hormone therapy use at their first semi-annual study visit. By 2017, the final year for this analysis, only 3% of postmenopausal with and without HIV-reported hormone therapy at their first semi-annual visit.
Associations with incident fracture
During the period of observation, incident fractures at any body site occurred in 17% and 15% of women with and without HIV, respectively (P = 0.09). Similarly, the incidence rate for fracture was 3.26 vs. 2.73 per 100 person-years for women with and without HIV, respectively (P = 0.22). Fragility fractures at the hip, spine, or wrist were uncommon and did not differ between women with and without HIV (Table 1). In bivariate analyses, race (white vs. black) and smoking (ever) were statistically associated with higher incident fracture (P ≤ 0.05), whereas HIV status and hormone therapy use were not (Table 2). In multivariate analyses, the above associations of white race and smoking with incident fracture remained statistically significant.
Introduction
With successful antiretroviral therapy (ART), over half of women living with HIV (WLWH) in the United States are at least 50 years old; many are transitioning through menopause. Menopause is marked by declining estrogen production and often accompanied by vasomotor symptoms (VMS), such as hot flushes and night sweats [1]. Women experience frequent VMS for 7.4 years on average, with black women having the most enduring VMS of any racial/ethnic group [2]. Some studies suggest that WLWH experience menopause at earlier ages [3-6] and VMS more commonly than women without HIV [7-10]. Bone loss accelerates substantially during the first 2 years of menopause and is a major risk factor for fractures in older age [11]. Fracture rates are 30-70% higher in older adults with HIV compared with the general population [12-14], and may be related to higher levels of pro-resorptive inflammatory cytokines, negative effects of specific ART on bone cells, and a higher prevalence of traditional osteoporosis risk factors [15].
Hormone therapy, given as estrogen-only therapy after hysterectomy or as estrogen with progestogen for women with an intact uterus, is considered the most effective treatment of VMS [16-18] and also prevents menopausal bone loss and decreases long-term risk of fracture [19-21]. However, menopausal hormone therapy is uncommon in the general population and among WLWH [22,23] because of lingering concerns about cardiovascular and breast cancer risk raised by the Women's Health Initiative studies [24-26]. We previously found that fracture rates were higher in WLWH than HIV-seronegative women of similar age in the Women's Interagency HIV Study (WIHS) [27]. In order to explore potential benefits of hormone therapy for WLWH, this analysis evaluates whether hormone therapy exposure reduces rate of fracture.
Hormone therapy and fractures in postmenopausal women
Yin, Michael T.a; Hoover, Donald R.b; Shi, Qiuhuc; Tien, Phyllis C.d,e; Cohen, Mardge H.f; Kassaye, Sebleg; Gustafson, Deborahh; Adimora, Adaorai; Weitzmann, M. Nealej,k; Bolivar, Hectorl; Warriner, Amym; Bares, Sara H.n; Sharma, Anjalio
Abstract
Background:
Fracture rates have been reported to be higher among older women living with HIV (WLWH) than HIV− women. Hormone therapy with estrogen can reduce vasomotor symptoms (VMS) associated with menopause and prevent fractures. As data are limited on the benefits of hormone therapy use in WLWH, we examined associations of hormone therapy, use and fractures.
Methods:
A prospective study of 1765 (1350 WLWH and 415 HIV−) postmenopausal Women's Interagency HIV Study (WIHS) participants was performed, including self-reported hormone therapy, use and fracture data from 2003 to 2017. Proportional hazard models determined predictors of new fractures at any site or at typical fragility fracture sites (hip, spine, wrist).
Results:
At the first postmenopausal visit, the median (IQR) age of WLWH was slightly younger than HIV− women [49.8 (46.4-53) vs. 50.7 (47.5-54), P = 0.0002] and a smaller proportion of WLWH reported presence of VMS (17% vs. 26%, P < 0.0001). A greater proportion of WLWH than HIV− women reported hormone therapy use (8% vs. 4%, P = 0.007) at the first postmenopausal visit. In multivariate analyses, white race and smoking were significant predictors of incident fracture at any site but hormone therapy (P = 0.69) and HIV status (P = 0.53) were not.
Conclusion:
Our study did not find evidence of benefit or harm with regards to fracture outcomes in postmenopausal WLWH receiving hormone therapy. Further research is needed to determine whether hormone therapy has benefits beyond treatment of VMS, such as prevention of adverse aging-associated outcomes.
Participant characteristics at postmenopausal visit
WLWH were younger than women without HIV (median age of 49.8 vs. 50.7, P = 0.0002) at the first postmenopausal visit (Table 1). WLWH were less likely to be non-Hispanic black (68% vs. 75%, P = 0.001) and have BMI greater than 30 kg/m2 than women without HIV (39% vs. 58%, P < 0.0001). WLWH were less likely to have diabetes mellitus (20% vs. 27%, P = 0.004) but more likely to have detectable HCV RNA (30% vs. 22%, P = 0.003) and eGFR less than 60 ml/min (11% vs. 6%, P = 0.002). WLWH were also less likely to report current smoking, heavy alcohol consumption, cocaine use than women without HIV, but more likely to report calcium supplementation (Table 1). Among WLWH at the index visit, median CD4+ T-cell count was 490 (288, 714 cells/μl), 82% reported ART use (including 41% on protease inhibitor and 38% on tenofovir disoproxil fumarate-containing regimens), and 65% had an HIV RNA less than 200 copies/ml on ART. WLWH who reported hormone therapy use at any time during the study period (n = 230) were younger, more likely to be white, to be a nonsmoker, and take calcium supplementation than WLWH who did not use hormone therapy (n = 1123) but did not differ in other respects at the first postmenopausal visit (Table S1, https://links.lww.com/QAD/C545).
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