Abstract & Commentary
By Leon Speroff, M, Professor of Obstetrics and Gynecology, Oregon Health & Science University, Portland. Dr. Speroff is a consultant for Barr Laboratories.
Synopsis: This study emphasizes the need for increased awareness and monitoring for the potential development of excessive suppression of bone turnover during long-term alendronate therapy.
Source: Odvina CV, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90:1294-1301.
Odvina and colleagues report 9 patients (8 women and 1 man) who sustained spontaneous, atraumatic, nonspinal fractures while on alendronate treatment. One patient also had a lumbar spinal fracture, but almost all of the fractures occurred in skeletal sites rich in cortical bone. In addition, 6 of the 9 patients displayed either delayed or absent fracture healing. The patients received the standard dose of either 10 mg/d or 70 mg/wk for 3 to 8 years. Estrogen was administered with the alendronate in 3 of the women and fractures occurred within 3 years, and glucocorticoids were used by 2 of the women. Tetracycline labeling demonstrated severe depression of bone formation in all 9 patients.
There is no doubt that bisphosphonate treatment prevents bone loss and reduces the incidence of fractures in women who already have osteoporosis. The concern is the use of bisphosphonates in younger postmenopausal women to prevent osteoporosis, a treatment that must be prolonged in order to be effective. This is not the first report of a possible adverse complication. Most impressive are the patients who developed osteonecrosis requiring removal of the jaw.1
Bisphosphonates (like estrogen and raloxifene) inhibit bone resorption, but inhibition of bone resorption also secondarily inhibits bone formation. The increase in measured bone density is because older bone is more dense than new bone. The potential risk that has been long recognized is that prolonged exposure to bisphosphonates or excessive dosage would oversuppress bone resorption, thus oversuppressing bone turnover and affecting the biomechanical strength of bone.
What are possible mechanisms for an adverse effect of long-term bisphosphonate treatment? Animal experiments indicate that alendronate inhibits the normal repair of microdamage, resulting eventually in the accumulation of microdamage and loss of bone strength. Another mechanism is chronic suppression of resorption and bone turnover allowing excessive mineralization and increasing brittleness of bone. The mechanism for overdosage can be the unique tight binding of bisphosphonates to bone causing this drug to remain in the body for decades. This is believed to be the explanation for why there is no rapid bone loss after discontinuing bisphosphonate treatment in contrast to the rapid loss that follows the termination of estrogen therapy. Thus, when bone remodeling releases bound bisphosphonate, it is free to be active again, and the result is the endogenous bisphosphonate is added to the administered bisphosphonate, raising dosage exposure. At this time, we don’t know the lowest effective dose and the lowest effective duration of exposure.
It is possible that this complication of bisphosphonate treatment is seen only in patients with concurrent diseases or in patients receiving concurrent estrogen therapy (combining the effects of 2 antiresorptive agents). But this is not known for certain, and our concern should not be limited to these instances. More importantly, how does this report jibe with the published results indicating long-term (10 years) safety of alendronate treatment?2 It will be at least another 10 years before we know whether negative effects due to bisphosphonate treatment have the potential to outweigh the beneficial effects.
It seems to me that several conclusions are warranted at this time:
1. An increased susceptibility to nonspinal fractures may occur relatively early when bisphosphonate treatment is combined with another antiresorptive treatment, and this should be avoided because no additional benefit on fracture risk has been demonstrated with combined treatment.
2. Bisphosphonate treatment is best reserved for older postmenopausal women. It is not a drug of choice for the prevention of osteoporosis in relatively young postmenopausal women.
3. In all patients being treated with bisphosphonates, it would be wise to consider a time limit for duration of exposure, perhaps 5 years.
1. Ruggiero SL, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates. J Oral Maxillofac Surg. 2004;62:527-534.
2. Bone HG, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-1199.