Combined Bisphosphonate and Hormone Treatment

Abstract & Commentary

Synopsis: Estrogen combined with risedronate increased bone mineral density slightly more than
estrogen alone.

Source: Harris ST, et al. J Clin Endocrinol Metab. 2001;86:1890-1897.

Harris and colleagues report the results of a multicenter, 1-year, double-blind, placebo-controlled study of the effect on bone mineral density of risedronate (5 mg daily) combined with conjugated estrogens (0.625 mg daily) compared with estrogen alone in a total of 524 women. Forty-eight percent of the patients also received medroxyprogesterone (5 mg) in a sequential regimen. At the end of 1 year, both treatment groups increased bone mineral density. (See Table).

Table-Gain in BMD with Treatment

Femoral spine

Midshaft neck


Hormone therapy alone




Combined risedronate & hormone therapy




The only differences that achieved statistical significance were those in the femoral neck and midshaft radius. Bone biopsies in a subset of patients demonstrated normal bone structure and mineralization in both groups. After 1 year, there were 4 new vertebral fractures (2.6%) in the hormone-only group and 3 (1.8%) with the combined treatment; however, this study had insufficient power to detect meaningful differences in fractures.


There is growing recognition that not all postmenopausal women respond to treatments aimed at the prevention of bone loss. Clinicians have rapidly assumed that the solution is to combine treatments. There are 2 important questions:

1. Will a slightly better gain in bone density mean better protection against fractures?

2. Will a poor responder to 1 treatment respond to an alternative treatment?

Adding alendronate or risedronate to postmenopausal hormone therapy produces a gain in bone density that is about 1-2% greater than with single treatment, indicating that each works through a different mechanism. There is no doubt that both lack of bone loss and a gain in bone mineral density correlate with a reduction in fractures. However, that does not mean that a 7% gain protects against fractures better than a 5% gain. One piece of evidence that suggests a difference in bone density is not the whole story is the fact that raloxifene produces a smaller increase in vertebral bone density compared with estrogen and alendronate, yet the 3 agents are associated with essentially identical reductions in vertebral fractures. No study, thus far, has had a sufficient number of patients followed long enough to provide reliable fracture information with combined therapy compared to single agent treatment.

The percentage of postmenopausal women who respond poorly to single agent treatment varies from 5-20% in various studies. This is a substantial number, and underscores the recommendation to screen 65-year-old women with bone density measurements even if they are on osteoporosis prevention treatment. This would detect the poor responders and provide the opportunity for intervention. However, studies of this group of women have yet to appear in the literature. At this time we can only provide the proper intervention, follow the patient, and learn from the patients.

Recommended Evaluation and Intervention for Poor Responders:

1. Rule out other causes of osteoporosis.

2. Make sure calcium and vitamin D supplementation is adequate.

3. Make sure compliance with the treatment is appropriate.

4. Add another antiresorptive agent to the treatment regimen.

5. After 2 years, assess bone density response.

The bone world has expressed concern that combining 2 agents that both inhibit bone resorption might over time interfere with the dynamics of bone remodeling and ultimately yield more fragile bone. This is speculation at the present time, and the biopsy results in this study indicating normal bone morphology and mineralization are reassuring. This has also been reported with combined alendronate and estrogen treatment.1 In addition, tetracycline labeling appeared in the biopsy specimens indicating that the necessary bone turnover to repair microdamage was taking place.

At the present time, it is premature to assume that combined agent therapy will yield better fracture protection. We need evidence from bigger studies with longer follow-up.


1. Bone HG, et al. J Clin Endocrinol Metab. 2000;85: 720-726.