Correspondence
Prolonged Bisphosphonate Release after Treatment in Children
N Engl J Med 2007; 356:1075-1076March 8, 2007
- Article
To the Editor:
Bisphosphonates are widely used in the management of osteoporosis. They are cleared rapidly from the circulation, with about half the administered dose taken up by the skeleton and the rest excreted unmetabolized by the kidneys.1 At the bone surface, bisphosphonates suppress bone resorption and are embedded in bone. The embedded bisphosphonate is released slowly from bone, presumably after the resumption of bone remodeling at previously exposed sites.
A terminal half-life of 10 years has been estimated for alendronate in the longest pharmacokinetic study in humans, up to 1.5 years, after intravenous administration. There is no direct evidence of release of bisphosphonates in patients who receive long-term, continuous oral treatment, the most common therapy for osteoporosis. Such information can help explain changes in bone remodeling and in bone mineral density after the cessation of long-term treatment and can be obtained by measuring the urinary excretion of bisphosphonates, the only route of their elimination from the body.
We measured drug excretion after the cessation of long-term treatment with daily oral pamidronate in seven young patients with severe osteoporosis — four with juvenile osteoporosis, two with osteogenesis imperfecta, and one with juvenile arthritis. All but one of the patients has been described previously2; all had normal renal function. At the start of treatment, the patients were between the ages of 10 and 14 years, and they received pamidronate for a mean period of 6.7 years (range, 4 to 10). Excretion of pamidronate was measured in 24-hour urine samples with the use of fluorometry and high-performance liquid chromatography at a mean interval of 7.7 years (range, 3 to 12) after treatment had been discontinued; the total mean observation period was 12.9 years (range, 7 to 19).
Pamidronate was detectable in urine samples from the patients up to 8 years after the cessation of treatment (Figure 1AFigure 1
Twenty-Four-Hour Urinary Excretion of Pamidronate in Seven Young Patients with Osteoporosis.). There was a trend toward reduced excretion of the drug with time, but there was no relation between the cumulative dose of the bisphosphonate and its excretion in urine (Figure 1B).These results provide direct evidence of long-term release of a bisphosphonate and show that the drug can persist in the body for many years after the discontinuation of treatment. The activity of the released bisphosphonate is unknown but may account for the stabilization of bone mineral density and fracture rates after the discontinuation of treatment in patients with osteoporosis.3,4 In addition, the findings suggest a need for caution in the selection of girls and young women for bisphosphonate treatment, since there is only anecdotal information about the safety of the drugs during fetal development.
Socrates E. Papapoulos, M.D., Ph.D.
Serge C.L.M. Cremers, Ph.D.
Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
s.e. papapoulos@lumc. nl Dr. Papapoulos reports receiving consulting fees from MSD, Procter & Gamble, and Roche–GlaxoSmithKline and serving on advisory boards for Merck, Novartis, Procter & Gamble, Sanofi-Aventis, and Roche–GlaxoSmithKline.
4 References1
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