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Date of release: 18 January, 2010

The effect of estrogen and alendronate on metaphyseal fracture healing in mice


A paper recently published by Kolios and colleagues addresses the effect of estrogen and alendronate on the healing of osteoporosis-related fractures in mice [1]. Three groups of ovariectomized mice and one control group received a soy-free diet. Two of the three groups of castrated mice additionally received either 17β-estradiol or alendronate in the diet. After 10 weeks, a metaphyseal tibia osteotomy and T-plate fixation were performed on all mice. After a 5-week healing period, the mice were sacrificed and the fracture callus was evaluated qualitatively by biomechanical bending and quantitatively by micro-radiographic sections. It was found that the 17β-estradiol-treated mice had superior biomechanical properties compared to all other groups and that this could be attributed to healing in the callus that occurred in a physiological fashion with improvement in the trabecular structure. The alendronate-treated group did not show these properties and results were only marginally better than the results in the ovariectomized mice that did not receive 17β-estradiol or alendronate but worse than the results in the control group. The authors conclude with a suggestion that a short treatment course with 17β-estradiol in the first weeks after fracture might be beneficial in humans. It is argued that, with such a limited (not defined) treatment course, benefits will outweigh negative effects.

Comment

The clinician must interpret the findings and recommendation of this animal study with caution. In humans, pharmacological agents are used to reduce the risk of fractures in patients at high risk of fracture. The efficacy of a drug is expressed as fracture risk reduction compared to placebo after a set period of time (usually 3 years). In this setting, the effect of 17β-estradiol [2] and alendronate [3] are both significantly better than placebo but no comparative head-to-head studies have been done. This study in mice does not measure anti-fracture efficacy but assesses the process of post-fracture healing selectively in the metaphyseal area of the tibia. The authors chose the tibial metaphyseal bone as the most suitable site to study considering the fact that osteoporosis strongly affects the metaphyseal trabecular structure and that osteoporosis heals predominantly endosteally. This site is very suitable to study the effect of 17β-estradiol, but not as suitable to study the effects of alendronate. Alendronate inhibits osteoclast-induced bone resorption, slows down bone turnover and increases bone mass, which result in an overall increase in bone strength. These effects are unlikely to be observed in metaphyseal bone after only 5 weeks of treatment. Present concerns regarding the use of alendronate pertain to the use of alendronate for periods of longer than 3–5 years in humans. Under these circumstances, it is postulated that over-suppression of bone turnover may cause osteonecrosis of the jaw [4] or lead to atypical fractures of the femur shaft [5]. It should be noted that the present study only evaluated the effect of a very short exposure to alendronate, a situation in humans that has not been associated with adverse effects on bone.
 
The results regarding the effect of 17β-estradiol on metaphyseal fracture healing in mice can be regarded as very encouraging and reaffirm the position of 17β-estradiol as nature’s own anti-osteoporotic agent. The improvement in trabecular microstructure is very important in the natural healing process of bone. The use of 17β-estradiol in osteoporosis is limited not by the effect on bone, but by possible side-effects, especially in the patient in whom treatment is initiated after the age of 60 years. Most patients presenting with an osteoporosis-related fracture will fall in this age category. As cardiovascular adverse events were increased in the Women’s Health Initiative study only in the first year of treatment with 17β-estradiol, I do not support the suggestion of a short treatment course with 17β-estradiol in the first weeks after fracture in patients naive to 17β-estradiol above the age of 60 years, irrespective of how short the treatment is. The IMS recommends that 17β-estradiol can be used in the woman at risk of fracture in the age group 50–60 years, that 17β-estradiol can be continued selectively after 60 years if the indication persists, but that 17β-estradiol should not be initiated after the age of 60 years. I believe that this recommendation is still valid [6].

Comentario

Tobie J. De Villiers
Panorama MediClinic and Department of Obstetrics & Gynecology, University of Stellenbosch, Cape Town, South Africa

    References

  1. Kolios L, Hoerster A, Sehmisch S, et al. Do estrogen and alendronate improve metaphyseal fracture healing when applied as osteoporosis prophylaxis? Calcif Tissue Int 2009 Dec 1. Epub ahead of print.
    http://www.ncbi.nlm.nih.gov/pubmed/19949941

  2. Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the Womens Health Initiative randomized trial. J Bone Miner Res 2006;21:817-28.
    http://www.ncbi.nlm.nih.gov/pubmed/16753012

  3. Wells GA, Cranney A, Peterson J, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 2008;1:CD001155.
    http://www.ncbi.nlm.nih.gov/pubmed/18253985

  4. Silverman SL, Landesberg R. Osteonecrosis of the jaw and the role of bisphosphonates: a critical review. Am J Med 2009;122)2 Suppl):S33-45.
    http://www.ncbi.nlm.nih.gov/pubmed/19187811

  5. Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res 2009;24:1095-102.
    http://www.ncbi.nlm.nih.gov/pubmed/19113931

  6. Pines A, Sturdee D, Birkhauser MH, et al. HRT in the early menopause: scientific evidence and common perceptions. Climacteric 2008;11:267-72.
    http://www.ncbi.nlm.nih.gov/pubmed/18645691