Comparison of Tibolone and Raloxifene on Bone Mineral Density in Osteopenic Postmenopausal Women

Condition(s) targeted: Osteoporosis; Osteopenia

Intervention: tibolone and raloxifen (Drug)

Phase: Phase 4

Status: Completed

Sponsored by: Organon

Official(s) and/or principal investigator(s):
Pierre D Delmas, Professor, Principal Investigator, Affiliation: Hopital Edouard Herriot pavilion F Lyon France

Both tibolone and raloxifene have been demonstrated to prevent postmenopausal bone loss. During treatment with tibolone bone mineral density (BMD) of the spine has been shown to be increased between 1. 8 and 5. 8 % above baseline in two years, depending on the population studied.

Since treatments aimed at prevention should ideally be used long-term, compliance with the treatment is crucial. Efficacy of and compliance with the two treatments will be measured and evaluated.

Official title: A Multinational, Randomized, Double-Blind, Parallel Group Comparative Trial on the Effects of 2 Years Treatment With Tibolone (1.25 mg Org OD 14) and Raloxifene (60 mg) on Bone Mineral Density in Osteopenic Postmenopausal Women

Study design: Treatment, Randomized, Double-Blind, Active Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: Measure BMD at screening after 52 weeks and after 104 weeks to evaluate the effects of treatment on bone mineral density of the lumbar vertebrae L1-L4

Secondary outcome:

To measure the effects on hot flushes by using diary booklets up to week 52,

To measure the economic impact during the whole trial period by using Medical resource utilization forms

at screening, week 52 and week 104:

bone mineral density of the total hip

A vaginal smear to determine vaginal atrophy,

at baseline, week 12, week 24, week 52 and week 104:

biochemical markers of bone metabolism

McCoy Female Sexuality Questionnaire, Short-Form to assess sexual functioning,

Women’s Health Questionnaire to assess quality of life,

Health Utility Index Mark 2 and 3 (HUI2/HUI3) to confirm the health status,

Detailed description: Osteoporosis is a major public health problem: half of all women risk developing osteoporosis

in later life and one in every three will break a bone 1. Between 5 - 20 per cent of people

suffering hip fractures will die within one year and more than half will be left disabled to some extent. In Europe, Japan and the United States an estimated 75 million people suffer from osteoporosis and, if present trends continue, the prevalence is expected to double by 2020. Prevention and protection of bone mineral loss is of the utmost importance. Historically hormone replacement therapy has been regarded by many as the first line treatment for the prevention of bone loss in postmenopausal women. It is one of the few accepted treatments, which reduces the incidence of fractures. Long-term compliance is essential since the benefits of hormone replacement do not continue once treatment is stopped. In addition to estrogens, new strategies for the prevention of osteoporosis have become available. These include selective estrogen receptor modulators (e. g. raloxifene), tibolone (a compound with tissue specific activity) and bisphosphonates. The objective of this trial is to compare these two treatment options namely tibolone, a compound with tissue specific activity, with raloxifene a SERM in the prevention of osteoporosis.

Furthermore, as continuation of treatment over the long-term is a pre-requisite in the prevention of osteoporosis, the adherence to treatment will be measured. The secondary objective will also be to evaluate their differential effect on well being by measurement of hot flushes, sexual function and quality of life. The health economic impact of these pharmacological agents is also of interest to many. In this particular trial, the health related costs of each treatment would be ascertained by means of a questionnaire.

Minimum age: 60 Years. Maximum age: 79 Years. Gender(s): Female.

Criteria:

Inclusion Criteria:

1. Only subjects who give voluntary written informed consent, and who are willing and able to make reasonable efforts to observe all clinical trial requirements are to be enrolled.

2. Subjects will be osteopenic but otherwise healthy postmenopausal women, from 60 to 79 years of age (inclusive) at entry.

3. Screening BMD of the lumbar vertebrae (L1-L4) must be between - 2. 5 SD and

- 1. 0 SD of the T-score.

4. Subjects should have a Body Mass Index (BMI) >19 and < 30 kg/m2.

Exclusion Criteria:

1. Spinal X-ray with symptomatic vertebral fracture (more than 20% reduction in expected vertebral height).

2. History of bilateral hip replacements.

3. Subjects who are not ambulatory.

4. History or presence of any malignancy, except non-melanoma skin cancers.

5. TVUS double wall thickness > 4 mm, or any other undiagnosed abnormalities visualized by TVUS.

6. Abnormal cervical Pap smear result

7. Undiagnosed abnormal (in the investigator’s opinion) vaginal bleeding in the past year prior to screening.

8. Mammography or physical examination finding that is suspicious of malignancy.

9. Uncontrolled hypertension

10. Bone disease other than osteoporosis such as Paget’s disease, osteomalacia or bone metastases.

11. Drinking more than 4 glasses of alcohol containing drinks per day.

12. Smoking more than 20 cigarettes a day.

13. Current or recent prolonged use of hepatic microsomal enzyme-inducing anticonvulsant medication or other drugs known to interfere with or otherwise alter the pharmacokinetics of steroids.

14. Treatment with anabolic steroids, calcitonin or raloxifene within the last 6 months.

15. Treatment with alendronate and risedronate more than 6 months. If treatment duration was less than 6 months a wash-out period of 12 months is necessary.

16. Treatment with etidronate for 1 year a wash-out period of 6 months is necessary. If treatment period of more than 1 year a wash-out period of 12 months is necessary.

17. Treatment with oral estrogen and/or progestin therapy (including contraceptives) or transdermal therapy and local estrogen applications within 6 months prior to screening/baseline BMD measurements (i. e. the wash-out period of 6 months must have been completed before the screening / baseline BMD assessments are made). A 20-week wash-out for injections of MPA-containing contraceptives (e. g. Depo- Provera®) is required.

18. Ever use of estrogen and/or progestin containing implants.

19. The use of cholesterol-lowering medicine cholestyramine or colestipol.

20. Subjects with a change in thyroid medication within the last 6 weeks prior to screening.

21. Subjects who have had fluoride treatment for 2 weeks or more (> 2 mg/day fluoride-ion) at any time (NaF tablets for caries prevention is allowed).

22. Subjects who have undergone systemic glucocorticoid treatment (> 5 mg prednisone or equivalent/day) for more than one month within the past 6 months (prior to BMD screening assessments).

23. Subjects who are receiving or require medication for the treatment of osteoporosis except Calcium / Vit D.

24. The use of coumarin products.

25. Type I diabetes mellitus.

26. Presence or history of thromboembolic disorders.

27. Serious decompensated renal or liver disease.

28. Abnormal laboratory values

29. Any condition or disease that could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the investigational product.

30. Use of investigational drugs within the past 30 days.

31. Subjects known to be hypersensitive to tibolone or raloxifene.

Organon Investigational Site, Prahran, Australia

Organon Investigational Site, Lyon, France

Organon Investigational Site, Hannover, Germany

Organon Investigational Site, Berlin, Germany

Organon Investigational Site, Verona, Italy

Organon Investigational Site, Siena, Italy

Organon Investigational Site, Charlotte, North Carolina 28212-2708, United States

Organon Investigational Site, Wyomissing, Pennsylvania 19610, United States

Starting date: October 2000
Ending date: February 2005
Last updated: February 2, 2007