Long Term Bisphosphonate Use

This study by Nelson B. Watts and Dima L. Diab from University of Cincinnati is an excellent review of the pharmacodynamics and pharmacokinetics of bisphosphonates and the effect of their long term use. I thought what was striking about this particular article are the recommendations of a drug holiday. This is something many have discussed previously but has not be published significantly.

"Bisphosphonates are popular and effective for treatment of osteoporosis. Because they accumulate in bone and provide some residual antifracture reduction when treatment is stopped, we recommend a drug holiday after 5–10 yr of bisphosphonate treatment. The duration of treatment and length of the holiday are based on fracture risk and pharmacokinetics of the bisphosphonate used. Patients at mild risk might stop treatment after 5 yr and remain off as long as bone mineral density is stable and no fractures occur. Higher risk patients should be treated for 10 yr, have a holiday of no more than a year or two, and perhaps be on a nonbisphosphonate treatment during that time."

Read the full article in Goodreader...

Bisphosphonates INCREASE osteoclast number?

A new study published in NEJM questions the long-held belief that bisphosphonate use promotes osteoclast apoptosis.
This study examined 51 bone-biopsy specimens obtained after a 3-year, double-blind, randomized, placebo-controlled, dose-ranging trial of oral alendronate to prevent bone resorption among healthy postmenopausal women 40 through 59 years of age. The patients were assigned to one of five groups: those receiving placebo for 3 years; alendronate at a dose of 1, 5, or 10 mg per day for 3 years; or alendronate at a dose of 20 mg per day for 2 years, followed by placebo for 1 year. Formalin-fixed, undecalcified planar sections were assessed by bone histomorphometric methods.

The Results were startling:
The number of osteoclasts was increased by a factor of 2.6 in patients receiving 10 mg of alendronate per day for 3 years as compared with the placebo group (P<0.01).> the number of osteoclasts increased as the cumulative dose of the drug increased (r=0.50, P<0.001).> of these osteoclasts were giant cells with pyknotic nuclei that were adjacent to superficial resorption cavities. Furthermore, giant, hypernucleated, detached osteoclasts with 20 to 40 nuclei were found after alendronate treatment had been discontinued for 1 year. Of these large cells, 20 to 37% were apoptotic, according to both their morphologic features and positive findings from in situ end labeling.

The discussion also has a great explanation as to why this may be occurring. It is too long to add here but to paraphrase, it appears the signal for the osteoclasts to undergo apoptosis is from the calcium they have just absorbed. Since the bisphosphonates inhibit this bone resoption, they stop the signal to enter into apoptosis.

Can read further here...