Postmenopausal Tibolone Therapy: Biologic Principles and Applied Clinical Practice

Morris Notelovitz, MD, PhD, MB, BCh, FACOG, FRCOG

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In This Article

Bone Health and Osteoporosis

The biology of bone remodeling and bone health is well defined. Estrogens and androgens play an important physiologic role in this process.[67] Together with good nutrition and appropriate exercise, both steroids are responsible for optimizing premenopausal bone formation, peak adult bone mass, and, consequently, greater bone strength.

Estrogen, progesterone, and androgen receptors are present in all bone cell types.[68,69,70] Osteoblasts express both ERalpha and ERbeta. ERalpha is the dominant ER in cortical bone and ERbeta in cancellous bone.[68] Estrogen suppresses the synthesis of cytokines responsible for stimulating osteoblast apoptosis and reducing osteoclast cell death.[71] Estrogen receptors are downregulated with aging and estrogen deprivation. Apoptosis of osteocytes is closely linked to estrogen withdrawal and may be one reason why mechanical loading does not prevent bone loss in the presence of low E2 levels.[72]

Estrogen is synthesized endogenously in bone tissue primarily via aromatization of testosterone to estradiol.[67] Osteoblasts also express sulfatase, 17beta-HSD type 2 and 17beta-HSD type 4 enzymes. The amount and ratio of these enzymes determine their activity and the bioconversion of inactive estrone sulfate to estrone and subsequently to intracellular estradiol. 17beta-HSD type 2 reduces the formation of estradiol by stimulating the conversion of E2 back to E1, whereas type 1 stimulates E2 formation from E1[73] (Figure 1).

The net clinical effect: estrogen is primarily an antiresorptive agent and therapeutically prevents osteoporosis by inhibiting bone resorption and bone turnover. Treatment with androgens stimulates new bone formation and results in higher bone mineral density than estrogen-alone therapy.[67]

Human osteoblasts express both PRA and PRB receptor activity via estrogen stimulation and through exclusive binding to the ERalpha.[74] The PR is upregulated only by cells that express ERalpha. A definitive therapeutic role for progesterone in bone remodeling has not been clearly defined.

A recent study confirmed earlier reports that tibolone increases bone mass and that this result is dose dependent.[75] The study was conducted in recently menopausal women (mean age ± 52 years) and demonstrated a highly significant treatment effect: the percentage increase from the baseline BMD of the spine following 0.625 mg,1.25 mg, and 2.5 mg of tibolone daily was 1.1%, 2.0%, and 2.6%. Subjects on 0.3 mg tibolone lost 0.4% and those on placebo lost 2.3%. A similar dose-related response was noted in the total hip BMD. Biomarkers of bone resorption also decreased from baseline according to dose. The enhancement of BMD in the spine and hip in this study was comparable to that of other agents in recently postmenopausal women: alendronate 5 mg and 10 mg daily (BMD > 1%-4% at lumbar spine and total hip)[76]; healthy postmenopausal women receiving 30-150mg raloxifene for 2 years (> BMD 1.3%-2.2% at spine ; 1.0%-1.5% for total hip)[77]; risedronate 5 mg daily in early postmenopausal women (1.4% > BMD of the lumbar spine).[78]

A placebo-controlled trial in older postmenopausal women (mean age ± 66 years) showed gains in the lumbar spine BMD above baseline of 5.9% (1.25 mg daily tibolone) and 5.1% (2.5 mg daily tibolone) after 2 years of therapy.[79] The placebo group (who received 400 mg calcium daily) maintained their lumbar spine bone mass (0.4%). In other studies, tibolone 2.5 mg daily significantly increased the BMD of the spine and the femoral neck (6.9% and 4.5%, respectively, over baseline) in osteoporotic postmenopausal women (mean age 65 years) with previous fractures[80]; a 10-year, prospective, nonrandomized study confirmed that 2.5 mg tibolone daily increases the BMD in the lumbar spine and femoral neck of postmenopausal women by 4.8% and 3.7%, respectively. The corresponding changes in the control population were -8.5% and -8.95%, respectively.[81]

A 2-year, blinded, randomized clinical trial compared the effectiveness on BMD and clinical tolerance of tibolone in 2 daily doses (2.5 mg and 1.25 mg daily) and on continuous combined hormone therapy (CCHT) (E2 2 mg; NETA 1 mg daily).[82] The proportion of responders (women whose BMD was > 2% after 2 years of treatment), was highest for women on E2/NETA (98.5%) compared with tibolone 2.5 mg (85.7%) and tibolone 1.25 mg (89.0%).

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