Women's Health Update: Osteoporosis, Part 2; Treatment Review; Estrogens, Progesterone, Phytoestrogens, Androgens, Bisphosphonat

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Women's Health Update: Osteoporosis, Part 2; Treatment Review; Estrogens, Progesterone, Phytoestrogens, Androgens, Bisphosphonates, Calcitonin

Estrogens

Estrogens have been used for decades in the treatment of women with osteoporosis. There is now a substantial amount of evidence that oral and transdermal preparations decrease postmenopausal bone loss, reduce the incidence of fracture, and prevent loss of height.( 1-4)

Frequently used estrogen regimens include: oral conjugated (Premarin); oral conjugated with medroxyprogesterone acetate (Prephase, Prempro); oral estropipiate (Ogen, Orthoest); transdermal estradiol (Estraderm); micronized estradiol (Estrace); oral ethinyl estradiol (Estinyl); conjugated equine estrogens with methyltestosterone (Estratest); natural estrogens (bio-identical estrone, estradiol, estriol)

Prescribing Natural Estrogens

Within the practice of alternative medicine, licensed practitioners give much attention to the use of natural estrogens. These are derived from diosgenin that is extracted from the Mexican wild yam and/or soybean. The diosgenin is then converted in the laboratory to bio-identical estrogens, either estriol, estrone, or estradiol. It is important to keep in mind several concepts when prescribing and formulating natural estrogens:

1. Estriol has not been shown to confer anti-resorptive properties. Estriol does interconvert with estrone and estradiol but we really do not know how much estriol it takes to convert to the other forms of estrogen.
2. The recommended minimum daily dose of conjugated estrogens for preventing bone loss is 0.625 mg per day. Utilizing natural estrogens should then theoretically follow similar dosage schedules. Therefore, the estrone and estradiol in a formula should add up close to 0.625 mg per day.
3. The popular practice of prescribing a tri-estrogen approach of 80% estriol/10% estrone/10% estradiol is uncertain as to whether it is based on urinary estrogen measurements or serum levels of post-menopausal women. Further research to validate this particular ratio and formulation is needed.
4. In a non-hysterectomized woman, always use a progesterone along with the estrogens. Oral micronized progesterone, 100 mg twice per day, has been documented in the PEPI trial to prevent endometrial hyperplasia.( 5) This is the only form of natural progesterone to date that has been studied and shown to adequately oppose the effect of estrogen on the uterus.
5. Consult a compounding pharmacy for assistance in formulations using natural estrogens.

Progesterone

A variety of progestational agents are currently available. These include: 17-hydroxyprogesterone; Medroxyprogesterone acetate; Norethindrone; Natural progesterone. Studies have shown that when administered alone, progestins preserve bone density and decrease the levels of biochemical markers of bone remodeling.( 6-8) Dr. John Lee cites many clinical examples that show some evidence to suggest transdermal natural progesterone will actively increase bone mass and bone density.( 9) He asserts that the more important factor in osteoporosis is the lack of progesterone, which causes a decrease in new bone formation 10 to 15 years before menopause. Due to anovulatory cycles in the late 30's and 40's, progesterone levels fall in postmenopausal women, and the additional effect of estrogen loss accelerates the loss of bone that has already begun premenopausally. Dr. Jerilyn Prior at the University of British Columbia found that female marathon runners developed osteoporosis while their est rogen level was high although they had stopped ovulating.( 10) Dr. Prior has also presented evidence that progesterone receptors exist in osteoblasts which are likely to enhance new bone formation.( 11)

Prescribing Natural Progesterone

1. When using topical creams or gels, confirm that you are getting natural progesterone versus Mexican Wild Yam extract. Some products contain 0-2 mg natural progesterone, others contain 2-15 mg natural progesterone per oz, and still others contain 600 mg or more per 2 oz. container. The typical daily dose is 1/4 tsp. twice per day of the higher strength products.
2. The typical oral dose of micronized natural progesterone is 100 mg twice per day.
3. Consult a compounding pharmacy for formulation advice.

Phytoestrogens

Soybeans contain phytoestrogens called isoflavones and a particular isoflavone called daidzein. Daidzein is similar in shape to a drug called Ipriflavone which is used in Europe to treat osteoporosis. Soy is the only dietary source of daidzein which is an non-steroidal estrogen-like molecule. Soy also increases the menstrual cycle length by 1 to 5 days, especially the follicular phase. This may have a positive effect on bone density due to longer exposure to elevated estrogen levels.

We now have animal data that daidzein and genistein (another isoflavone) directly stop bone demineralization. In addition to its phytoestrogen content, soy protein isolates conserve body calcium by diminishing calcium excretion in the urine. There is a similarity in structure between isoflavones and estrogen. In postmenopausal women, phytoestrogens act as estrogen agonists and antagonists, depending on the tissue site. We can speculate that given in enough quantity and over a long enough period of time, they would have an effect on bone mass. Much like the drug Tamoxifen as a beneficial effect on bone density with simultaneous anti-estrogenic effects in breast tissue, medicinal and dietary phyotestrogens may offer these same benefits.

Evidence to support the use of botanical medicines that contain phytoestrogens for prevention and treatment of osteoporosis is currently theoretical and speculative. Even when phytoestrogens relieve menopause symptoms of hot flashes, mood swings, insomnia, etc., this is not confirmatory for their effect on bone mass.

Androgens

Interest in the therapeutic potential of androgens has been based on two observations: 1) Circulating androgen levels are lower in postmenopausal women with osteoporosis, and 2) androgens may stimulate osteoblasts to differentiate and proliferate in vitro.( 12) Treatment with androgen derivatives, such as anabolic steroids, have been reported to increase bone density of the forearm, femoral diaphysis, and vertebrae, as well as elevate total body calcium.( 13-16) The total amount of testosterone produced after menopause is reduced; however, it is not due to decreased secretion by the ovaries. In fact, testosterone secretion by the postmenopausal ovary, in most women, is greater than that of a premenopausal ovary. Peripheral conversion of androstenedione, which is secreted by both the ovaries and the adrenal gland, accounts for 50% of the total testosterone production in females. The only randomized study to look at the possible benefit in osteoporosis using exogenous testosterone w as in 1986.( 17) Bone density results were compared when implants of 50 mg of estrogen alone were used vs. 50 mg of estrogen plus 100 mg of testosterone. After three years, the estrogen alone group showed no change, whereas the group receiving combined therapy showed an increase in bone mass of 2% at the metacarpal bone. This bone is not at risk for osteoporosis. In 1992 another study looked at bone density of women on oral estrogen only, compared to subcutaneous estrogen and testosterone. There was a significant increase in bone density of 5.7% at the spine, and 5.2% at the neck of the femur for those women on the combined therapy. The bone density of the women on estrogen only remained unchanged.18

Bisphosphonates

Bisphosphonates are chemical compounds and are analogues pyrophosphate of inorganic pyrophosphate. They reduce bone resorption by inhibiting osteoclast activity. Unfortunately, some bisphosphonates also inhibit the mineralization of newly synthesized bone matrix. Studies have shown a mean increase in bone density of 7 to 10% in the lumbar spine, 5 to 6% in the femoral neck, and 7 to 8% in the hip trochanter with bisphosphonates alone as compared to placebo.( 19) These increases in bone density were accompanied by reduced incidence of vertebral fracture and a decrease in height loss. For the naturopathic physician, a referral for the use of bisphosphonates would be considered in cases of severe osteoporosis and in cases who were at high risk and were either nonresponsive to other therapies, or where hormonal therapy was not tolerated or was contraindicated.

Calcitonin

Calcitonin is a peptide hormone that inhibits bone resorption. Subcutaneous or intranasal salmon calcitonin and subcutaneous human calcitonin have been demonstrated to be effective in the treatment of osteoporosis.( 20) Several studies have concluded that calcitonin therapy also reduces the incidence of fractures of the hip, vertebrae, and forearm.( 21, 22)

Therapeutic Scheme for Menopause Management Relative to Osteoporosis

A. Determine risk for osteoporosis: mild, moderate, severe. Use subjective medical history risk factors as well as objective measurements (height, bone density tests, urinary collagen breakdown markers, chemistry screen).

B. Be aware of six levels of intervention that cover the majority of clinical situations:

1. Diet, exercise, lifestyle, stress management
2. Nutritional supplementation
3. Botanicals
4. Natural estrogens and progesterone
5. Friendlier conventional hormone replacement (patch, estropipate, micronized estradiol)
6. Less friendly conventional hormone replacement (conjugated equine estrogens, ethinyl estradiol, medroxyprogesterone acetate, 17 hydroxyprogesterone, norethindrone

C. Recommendations according to risk: Mild: Use 1,2,3; Moderate: Use 1,2,4; Severe: Use 1,2,5 (with natural progesterone).

Prevention

The most effective approach to osteoporosis is prevention. To maximize peak bone mass, good lifestyle and habits, proper nutrition with a whole food vegetarian-based diet, regular moderate exercise, avoiding tobacco and minimizing alcohol should begin during childhood and adolescence and continue throughout life. Work with each individual to help them in optimal health habits.

Conclusion

Osteoporosis has a potentially devastating impact on the lives of patients as well as an economic impact of this preventable disease on the health care system. With the keen clinical skills of a good medical history, physical exam, laboratory testing, and bone density testing, the diagnosis of osteoporosis can be determined early, and corrective interventions can be used appropriately. With this awareness and commitment by physicians, the pain and suffering and death caused by osteoporosis can and will be greatly reduced.
References

(1.) Nachtigal LE, Nachtigall RH, Nachtigal RD, et al. Estrogen replacement therapy, I. A 10-year prospective study in the relationship to osteoporosis. Obstet Gynecol 1979; 53:277-281.

(2.) Ettinger B, Genant HK, Cann CE. Long term estrogen replacement therapy prevents bone loss and fractures. Ann Intern Med. 1985;102:319-324.

(3.) Weiss NS, Ure CL, Ballard JH, Williams AR, Jr. Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen. N Engl J Med. 1980; 303; 1195-1198.

(4.) Lufkin EG, Wahner HW, O'Fallon WM, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med. 1992; 1171; 1-9.

(5.) Writing Group for the PEPT Trial. The Effects of Estrogen or Estrogen/Progestin Regimens on Heart Disease Risk Factors in Postmenopausal Women. JAMA, January 18, 1996; Vol. 273, No. 3: 199-208.

(6.) Dequeker J, De Muylder E. Long-term progestogen treatment and remodeling in peri-menopausal women: a longitudinal study. Maturitas 1982; 4:309-313.

(7.) Abdalla HI, Hart DM, Lindsay R, et al. Prevention of bone mineral loss in postmenopausal women by norethisterone. Obstet Gynecol. 1985; 66:789-792.

(8.) Mandel FP, Davidson JB, Erlik Y, Judd HL, Meldrum DR. Effects of progestins on bone metabolism in postmenopausal women. J Reprod Med. 1982; 27 (suppl 18): 511-514.

(9.) Lee J. What Your Doctor May Not Tell You About Menopause. Warner Books, 1996: 166-167.

(10.) Ibid, 162-163.

(11.) Prior JC, Viana Y, Alojado N. Progesterone and the prevention of osteoporosis. Canadian J of Ob/Gyn and Women's Health Care 1991; Vol. 3; 4:178-184.

(12.) Kasperk C, Fitzsimmons R, Strong D, et al. Studies of the mechanism by which androgens enhance mitogenesis and differentiation in bone cells. J Clin Endocrinol Metab. 1990;71: 1322-1329.

(13.) Johansen JS, Hassager C, Pdenphant J, et al. Treatment of postmenopausal osteoporosis: Is the anabolic steroid nandrolone decanoate a candidate? Bone Miner. 1989; 6:77-86.

(14.) Geusens P, kDqqueker J, Verstraten A, et al. Bone mineral content, cortical thickness and fracture rate in osteoporotic women after withdrawal of treatment with nandrolone decanoate, I-alpha hydroxyvitamin D3, or Intermittent calcium Infusions. Maturitas 1986; 8:281-289.

(15.) Gennari C, Agnusdel D, Gonelli S, et al. Effects of nandrolone decanoate therapy on bone mass and calcium metabolism in women with established post-menopausal osteoporosis; a double-blind placebo-controlled study. Maturitas 1989; 11:1187-197.

(16.) Chesnut CH, Ivey JL, Bruber HE, et al. Stanozolol in postmenopausal osteoporosis; therapeutic efficacy and possible mechanisms of action. Metabolism 1983; 32:571-580.

(17.) Haffner SM and Valdez RA. Endogenous sex hormones; Impact on lipids, lipoprotein and steroid levels in postmenopausal women. Acta Endocrinol 1986;11:419-423.

(18.) Savvas M et al. Increase in bone mass after one year of percutaneous oestradiol and testosterone implants in postmenopausal women who have previously received long-term oral oestrogens. Br J Obstet Gynaecol 1992 Sept; 99(9): 757-60.

(19.) Liberman, U et al. Effect of oral alendromate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. NEJM 1995 Nov 30; 333(22): 1437-143.

(20.) Civitelli R, Gonnelli S, Zacchel F, et al. Bone turnover in postmenopausal osteoporosis: effect of calcitonin treatment. J Clin Invest, 1988; 82:1268-1274

(21.) Ivergaard JM, Gabseb NA, Hebseb SB, Christiansen C. Effect of calcitonin given intranasally on bone mass and fracture rates in established osteoporosis; a dose-response study. Br Med J 1992;305:556-561.

(22.) Rico H, Hernandez ER, Revma M, Gomez-Castresana F. Salmon cacitonin reduces vertebral fracture rate in postmenopausal crush fracture syndrome. Bone Miner. 1992; 16:131-138.

Townsend Letter for Doctors & Patients.

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By Tori Hudson

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