Half of American women over the age of 50 will develop osteoporosis, and 80% of Americans with osteoporosis are female, according to the Bone Health and Osteoporosis Foundation. Besides being female, other risk factors include white or Asian ethnic background, small frame, family history, smoking, excessive alcohol intake, corticosteroid use, sedentary lifestyle, and low hormone levels. In fact, the decline in estrogen levels around the time of menopause has been shown to accelerate bone loss. While females account for most cases of osteoporosis, up to 1 in 4 males over the age of 50 will suffer a fracture due to osteoporosis, and males are more likely than females to die within a year of a hip fracture due to related issues (Adler RA). Beyond age 70, men and women are at the same risk of developing osteoporosis. Risk factors for osteoporosis are similar between females and males, although males also have increased risk when they have below normal levels of testosterone.
Hormones and Bone Density in Women
Hormone replacement therapy (HRT) utilizing oral conjugated equine estrogens with or without medroxyprogesterone acetate used to be a first-line therapy both in preventing and treating postmenopausal osteoporosis. This type of HRT was shown to reduce hip and vertebral fracture risk in the Women’s Health Initiative study (WHI). However, providers may hesitate to prescribe HRT due to the increased risk of breast cancer, stroke, and venous thromboembolism found to be associated with equine estrogens and artificial progestins delivered orally.
Fortunately, there are safer forms of hormones and better delivery methods, such as bioidentical transdermal estradiol, that have not been shown to contribute to the same risks as oral HRT (Trémollieres FA et al). In a meta-analysis of randomized and prospective clinical trials, transdermal estradiol was shown to increase the lumbar spine bone mineral density (BMD) over baseline values in postmenopausal women after one and two years of use by 3.4% (95% CI: 1.7-5.1) and 3.7% (95% CI: 1.7-5.7), respectively (Abdi F et al.). Estradiol improves BMD because it promotes the activity of osteoblasts, the cells in bone that synthesize and mineralize bone.
Progesterone is also an essential hormone in bone health because it impacts osteoblast differentiation. The effects may be dose dependent as in vitro research demonstrated that physiologic doses of progesterone increased osteoblast differentiation, but supraphysiologic doses suppress this activity (Schmidmayr M et al.). Among over one-hundred postmenopausal women with osteoporosis treated in a clinical setting, 15 to 20 milligrams per day of transdermal progesterone was shown to increase BMD and decrease the chances of fractures (Lee JR). Combining a progestogen with estrogen therapy has been shown to create a more significant increase in BMD when compared to unopposed estrogen and controls (1.7% increase per year in BMD compared to placebo vs 1.3% increase, respectively). (Seifert-Klauss et al)
Testosterone and Bone Density in Men
The association between testosterone deficiency and lower bone density in men is thought to be due to a resulting lack of estradiol. Estrogen is derived from the aromatization of androgens like testosterone. In adults, testosterone stimulates periosteal growth and estrogen helps to maintain trabecular bone mass and structure. Up to 20% of men with symptomatic vertebral fractures and 50% of elderly men with hip fractures have low testosterone (PMID: 19011293). Fracture risk in males has also been tied to low estradiol levels. (PMID: 23329464). Evaluation for any male patient with osteoporosis should include assessing for etiological factors such as low testosterone levels, which occur in up to 15% of males with osteoporosis (PMID 23587643). In a randomized, controlled trial involving 70 men over age 65, testosterone replacement therapy for 36 months was shown to significantly increase BMD at the lumbar spine and in the hip compared to placebo (PMID: 14764753).
Risks of HRT vs Bioidentical and Transdermal Hormones
Although bioidentical hormone therapy has not been as extensively studied as HRT (oral estrogens and progestins), trends in the available research show that the risks of venous thromboembolism and breast cancer associated with oral forms of HRT do not seem to apply to transdermal estrogens or bioidentical progesterone.
The Million Women Study, which followed over one million women for an average of 3.1 years, demonstrated that venous thromboembolism risk increased with current use of oral but not transdermal estrogen (relative risk: 1.42 [95% CI: 1.22-1.66] vs 0.82 [95% CI: 0.64-1.06]) (Sweetland S et al).
The French E3N cohort study (N=80,377 postmenopausal women) found that breast cancer risk was significantly increased with progestin use but was unaffected by progesterone supplementation. “The relative risk was 1.00 (0.83-1.22) for estrogen-progesterone, 1.16 (0.94-1.43) for estrogen-dydrogesterone, and 1.69 (1.50-1.91) for estrogen combined with other progestogens. (Fournier A et al)
Progestins (norpregnane derivatives) increased the risk of thrombogenic events four-fold, while bioidentical progesterone was shown to have no thrombogenic effect in the ESTHER Study, a multicenter case-control study (Canonico M et al).
BHRT vs HRT, which is more effective at preventing osteoporosis?
Not only has transdermal hormone supplementation been shown to be safer than oral (Fournier A et al; Canonico M et al), but research has also shown that transdermal delivery can outperform oral forms in osteoporosis prevention with faster, better results and less unwanted effects. A small, single blind study involving 210 women between the ages of 48 and 55 compared vertebral body bone mineral density after of 1, 3, or 5 years of treatment with either placebo, oral estrogens plus levonorgestrel, or transdermal micronized estradiol plus progesterone (MHRT). Treatments were given for 22 days followed by a 7-day treatment-free interval to induce menstruation. No increase in BMD was observed in the control group. However, BMD of the vertebral bodies was significantly higher after 3 and 5 years in the oral hormone therapy group (p < 0.05), and after 1 year in the transdermal micronized hormones group (p < 0.01). (von Mach-Szczypiński J et al)
This increase was even more significant (p < 0.001) after 3 and 5 years in the transdermal group. The researchers concluded that transdermal micronized estradiol plus progesterone is “the treatment of choice in postmenopausal osteoporosis.” At the five-year point, oral hormone therapy was associated with numerous adverse effects including “hyperprolactinemia in 25%, arterial hypertension in 11%, elevated serotonin concentration in 11.5%, mammary cysts in 9.8%, mammary fibrocystic lesions in 11.3%, and benign endometrial hyperplasia in 9.7% of the cases. In contrast, mammary cysts were seen in just 2.3% of women receiving transcutaneous MHRT.”
Are bioidentical hormones FDA-approved?
Hormone therapy is approved by the FDA for the prevention of osteoporosis and to reduce the risk of fractures in postmenopausal females. This includes non-bioidentical and bioidentical forms of estrogens. In fact, the transdermal estradiol patch (Vivelle-dot) was FDA approved for prevention of osteoporosis in postmenopausal females in the year 2000.
Here is a comprehensive list of estrogens and progestogens that have been FDA-approved to treat menopausal symptoms: https://www.fda.gov/consumers/free-publications-women/menopause-medicines-help-you (access verified 4/17/2023). There are numerous bioidentical estrogens included – if the generic name of the drug is “estradiol” it is bioidentical. There is one approved bioidentical progestogen, Prometrium, which is oral micronized progesterone.
Often overlooked in the discussion of bone health, BHRT has been shown to be an effective means of maintaining and building bone in postmenopausal females and preventing fractures in males. Measuring saliva levels of free estradiol, progesterone, and testosterone is an important first step in bone risk assessment.
