Research: Progesterone & Bone Health
Overview
Bone loss, leading to reduced bone mineral density (BMD) and eventually osteoporosis, is the result when osteoclast-mediated bone resorption and osteoblast-mediated bone formation become unbalanced. In the normal state, the bone is in a state of homeostasis in which bone is formed at the same rate as it is resorbed (i.e., broken down to release calcium into the bloodstream, which is a mechanism for maintaining blood calcium levels) and this is referred to as “bone turnover”. Hormones play a significant role in these processes. Progesterone has bone-forming activity by binding to receptors on the osteoblasts. This explains the decreases in spinal bone density seen in premenopausal women with low progesterone levels (see Prior 1990, below). In the Michigan Bone Health Study, those premenopausal women with the lowest bone mass had the highest rates of progesterone deficiency (see Sowers 1998 below).
The effects of progesterone and estrogen on bone are synergistic and complementary to each other, and some clinical trials have found greater increases in spinal BMD when the progestin medroxyprogesterone acetate (MPA) is added to estrogens than with estrogens alone. However, fracture risk data for conjugated equine estrogens (CEE) and CEE/MPA were not analyzed separately in the Women’s Health Initiative study, which reported a reduction in fractures with hormone therapy. The wide variation in synthetic progestins and progesterone formulations has hindered the statistical power of meta-analyses to detect the effects on BMD of the progesterone/progestin component of hormone therapy, but tibolone (a synthetic progestin widely used in Europe but not approved in the US) was shown to have similar effects on BMD to any estrogen compound in one meta-analysis (see Dören 2003). At the time of the menopausal transition, the rate of bone turnover is still high and so progesterone’s bone-forming effects are harder to see. However, longer term studies of progesterone treatment, currently in progress, may further confirm the benefit of this hormone for maintenance of bone density after the first few years following the onset of menopause.
Research
- Dören M, Nilsson J-A, Johnell O. Effects of specific post-menopausal hormone therapies on bone mineral density in post-menopausal women: a meta-analysis. Human Reprod 2003; 18(8):1737-1746.
- Liang M, Liao EY, Xu X, Luo XH, Xiao XH. Effects of progesterone and 18-methyl levonorgestrel on osteoblastic cells. Endocr Res . 2003 Nov;29(4):483-501.
The authors evaluated in this study the effects of progesterone (P4) and levonorgestrel (LNG) on markers of bone growth, utilizing normal human osteoblasts as well as the osteosarcoma cell line, MG-63. Their study found that, compared with placebo, both P4 and LNG increased the proliferation and differentiation of human osteoblasts through osteocalcin gene transcription.
- Sowers M, Randolph JF Jr, Crutchfield M, Jannausch ML, Shapiro B, Zhang B, La Pietra M. Urinary ovarian and gonadotropin hormone levels in premenopausal women with low bone mass. J Bone Miner Res 1998; 13(7):1191-202.
- Prior JC, Vigna Y, Alojado N. Progesterone and the prevention of osteoporosis. Canadian Journal of Obstetrics/Gynecology and Women’s Health Care 1991; 3(4):178-84.
In this review article, the authors propose that cyclic progesterone both prevents bone loss and acts as a bone-builder. The studies discussed focus on abnormal menstrual cycles as an important risk factor for osteoporotic fractures. Their conclusion is that the first step in preventing osteoporosis is treating ovulation disorders.
- Prior JC, Vigna YM, Schecter MI, Burgess AE. Spinal bone loss and ovulatory disturbances. New England Journal of Medicine 1990; 323(18):1221-7.
A review of the available data indicates that progesterone acts to promote bone metabolism. It appears to be independent of estrogen by either acting directly at progesterone receptors, or indirectly through competition at glucocorticoid receptors in the osteoblasts.
- Prior JC. Progesterone as a bone-trophic hormone. Endocr Rev 1990; 11(2):386-98.
- Lee JR. Osteoporosis reversal; the role of progesterone. International Clinical Nutrition Review 1990;10(3):384-91.
Transdermal progesterone supplementation with and without conjugated estrogens was evaluated in a clinical setting using 100 women aged 38 to 83 years. The average time from onset of menopause was 16 years. 63 women were followed for three years with dual photon absorptiometry. Treatment also included dietary changes, nutritional supplements, and exercise. All individuals followed showed an increase in bone mineral density over the three years, with the greatest increase occurring in the first year. There was no difference noted between estrogen/progesterone and progesterone only groups. Subjective changes included increased libido, diminished hot flushes, reduced joint pain, and increased mobility and energy. No side effects were noted during treatment protocol.
