Comparisons between orally administered pill and transdermal patch suggests that when estrogens are taken orally the risks of thrombophlebitis and pulmonary embolism are increased, an effect which is not seen with topical administration. Transdermal and transvaginal administration are not subject to first pass metabolism , and so lack the anabolic effects that oral therapy has on hepatic synthesis of Vitamin K dependent clotting factors .  This effect refers only to patches for post menopausal hormone replacement, which contain estradiol , not those used in oral contraceptive therapy, which contain ethinylestradiol . The latter is associated with an increased incidence of venous clot.  The WHI also showed an increased incidence arterial disease, namely stroke, in patients who began HRT after the age of 65, although this effect was not significantly present in those who began therapy during their fifth decade.
Osteoporosis is also a global problem. Worldwide, one third of women aged 60-70 years and two thirds of women 80 years or older are estimated to have osteoporosis. In several European countries, women older than 45 years spend more time in the hospital for osteoporosis-related problems than for any other disease. In the next 50 years, the number of hip fractures for both men and women will more than double. According to the World Health Organization (WHO), osteoporosis is the second leading healthcare problem after cardiovascular disease. In France, Germany, Italy, the United States, the United Kingdom, Spain, and Japan, fewer than half of women with osteoporosis are diagnosed.