Questions over Fosamax (alendronate) long-term data

[Guest guest]

Questions over alendronate long-term data

Rheumawire

Jul 8, 2004

Zosia Chustecka

The recent publication of 10-year data on alendronate (Fosamax, Merck &

Co) in the treatment of osteoporosis [1] has prompted a flurry of

correspondence on the subject in this week's New England Journal of

Medicine, with 2 letters questioning the long-term data on safety and

efficacy of the higher doses, and 1 highlighting a potential

complication of treatmentoral osteonecrosis.

" Recently at our institution, there has been growing concern about the

delayed bone healing and osteonecrosis of the jaws in association with

the use of bisphosphonates, " says Dr Salvatore Ruggiero and Bhoomi

Mehrotra (Long Island Jewish Medical Center, New Hyde Park, NY) [2].

" The typical presentation is a nonhealing tooth-extraction socket or

exposed jawbone, both of which appear to be refractory to conservative

debridement and antibiotic therapy. "

Bisphosphonate treatment was the only common factor in a series of 63

cases that Ruggiero and colleagues reported recently, in the May 2004

issue of the Journal of Oral and Maxillofacial Surgery [3]. " We were

struck in the past 3 years with a cluster of patients with necrotic

lesions in the jaw, who shared 1 common clinical feature, that they all

received chronic bisphosphonate therapy. The necrosis that was detected

was otherwise typical of osteoradionecrosis, an entity that we rarely

encountered at our center, with fewer than 2 patients presenting with a

similar manifestation per year, " they write. The majority of these

patients required surgical procedures to remove the involved bone, they

add.

Most of these patients were receiving high-dose intravenous

bisphosphonates for the treatment of bone metastases. Examination of

biopsy specimens of jaw lesions showed no evidence of metastatic

disease, the researchers note. However, 10 of these patients were

receiving bisphosphonate for the treatment of osteoporosis (oral

preparations in 8, intravenous in 2).

" In view of the current trend of increasing and widespread use of

chronic bisphosphonate therapy, our observation of an associated risk of

osteonecrosis of the jaw should alert practitioners to monitor for this

previously unrecognized potential complication. An early diagnosis might

prevent or reduce the morbidity resulting from advanced destructive

lesions of the jawbone, " Ruggiero et al conclude. Ruggiero tells

rheumawire that since their report was published in May, his team has

seen a further 15 patients with this complication, and has heard of

several others from other physicians.

However, in a response, 2 of the authors of the original report, Dr

Henry Bone (Michigan Bone and Mineral Clinic, Detroit) and Dr Arthur

Santora (Merck & Co, Rahway, NJ) note that no similar cases have been

identified in any clinical trials with alendronate, nor was

osteonecrosis observed in preclinical studies, which included very high

exposures to the drug [4]. They also point out that most of the cases

that Ruggiero et al report were seen in patients with cancer that had

metastasized to bone, and so these patients also had many other possible

risk factors, including chemotherapy, glucocorticosteroid exposure,

recent dental alveolar procedures, etc.

" In view of the very large numbers of persons who have been treated with

alendronate (for an estimated 20-million patient-years), a careful,

systematic, epidemiological approach will be needed to distinguish

between chance association and a causal relationship, " they comment.

Alendronate is approved for use in the treatment of postmenopausal

osteoporosis at a recommended dose of 10 mg daily (and also a recently

approved 70-mg once-weekly version). However, the 10-year data on

alendronate come from a follow-up of an old study, in which various

doses were investigated (5 mg, 10 mg, and 20 mg daily). Two of the

letters question the safety and efficacy of the higher doses of the

drug.

The long retention time of alendronate in the bone was presented as an

advantage, but Dr Nina Bjarnason (Institute for Rational

Pharmacotherapy, Copenhagen, Denmark) suggests that it raises a question

over the drug's long-term safety [5]. " What the present study actually

shows is that 2 years of therapy with alendronate 20 mg followed by 3

years' treatment with 5 mg suppresses bone turnover to a degree from

which it may not recover, " she maintains.

" This result is consistent with data from a study in Danish women [6],

which showed that 2 years of treatment with 20-mg alendronate led to a

reduction in bone turnover that did not return to baseline 5 years after

the discontinuation of therapy, " Bjarnason writes. This contrasts with

the data from another study [7], which used lower doses of alendronate,

2.5 mg and 5 mg, and showed that bone turnover returned to placebo

levels 2 years after discontinuation of the drug.

" Thus, the long-term safety of 20-mg alendronate has not been

established, " Bjarnason concludes. In response, Bone and Santora point

out that the 20-mg daily dose of alendronate is not currently

recommended. In their study, it showed no apparent advantage over the

lower doses.

" The optimal dose of bisphosphonate for preventing fractures has not yet

been determined, " says Dr Ott (University of Washington, Seattle)

[8]. She notes that with alendronate, there was no significant

differences in the rate of fracture between 5-mg and 10-mg doses, either

during the first 3 years or during years 6 through 10, although she adds

that it's difficult to evaluate these data as the 2 groups started off

with different baseline fracture prevalence rates. Ott also cites a

study with another product, risedronate (Actonel, Procter & Gamble) in

5445 women with osteoporosis [9], in which the lower dose of 2.5-mg

daily risedronate significantly decreased the incidence of hip fracture,

but the higher dose of 5-mg did not.

" Fractures are more important than bone density, " says Ott. " Despite the

reassuring data from the report by Bone et al, questions remain about

the possible brittleness of the bones in the second decade of

bisphosphonate use. " In addition, she points out that patients with

bisphosphonate accumulation may lose their capacity to benefit from

newer anabolic agents, such as parathyroid hormone. " Thus, I see no

clear advantage of using the higher doses, " Ott concludes, and she

suggests prescribing alendronate at a dose of 35 mg per week. (This is

half that currently recommended for the treatment of osteoporosis,

although this is the dose that is currently recommended for use in the

prevention of osteoporosis).

Bone and Santora respond by pointing out that their study did not have

adequate statistical power to compare fracture rates between doses of 5

mg and 10 mg daily, so they limited their analyses to turnover and

bone-density end points, which appeared to favor the 10-mg regimen.

Elaborating on her comments to rheumawire, Ott says: " I think there must

be more focus on preventing fractures. The clinically important goal of

osteoporosis treatment is to prevent another fracture, not to increase

the bone density. As I wrote in my letter, there have already been large

studies showing that somewhat lower doses of bisphosphonates can prevent

fragility fractures as well as the higher doses. A general principle of

medicine is to use the lowest effective dose of any medication.

" The bisphosphonates work by blocking bone resorption, so once the bone

resorption has decreased to an optimal level, there is theoretically no

benefit to keep decreasing it, " she commented. " I did not have room in

my letter to discuss the Fracture Intervention Trial, one of the largest

studies of alendronate. " There were about 2000 women who had

osteoporosis and compression fractures, and the group given alendronate

had significantly fewer fractures than the placebo group.

The dose was only 5 mg/day for the first 2 years (during which fracture

benefit was seen), and then for the last year the dose was increased to

10 mg/day. " We don't know what would have happened the third year if

these women had remained on 5 mg/day, but I hypothesize they would have

had the same number of new fractures as they did on 10 mg/day. "

Ott summarizes her comments by saying: " Again, my main points are that

physicians should focus on fractures and that we still do not really

know about long-term effects of these relatively new medications. "

Sources

Bone HG, Hosking D, Devogelaer JP, et al. Ten years'

experience with alendronate for osteoporosis in postmenopausal women. N

Eng J Med 2004; 350:1189-1199.

Ruggiero R and Mehrotra B. Ten years' experience with

alendronate for osteoporosis in postmenopausal women [correspondence].

N Engl J Med 2004; 351:191.

Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL.

Osteonecrosis of the jaw associated with the use of bisphoshonates: a

review of 63 cases. J Oral Maxillofac Surg 2004; 62:527-534.

Bone HG and Santora AC. Author reply. N Eng J Med

2004; 350:191-192.

Bjarnason NH. Ten years' experience with alendronate

for osteoporosis in postmenopausal women [correspondence]. N Eng J Med

2004; 350:190.

Bagger YZ, Tanko LB, sen P, et al.

Alendronate has a residual effect on bone mass in postmenopausal Danish

women up to 7 years after treatment withdrawal. Bone 2003; 33:301-307.

Ravn P, Bidstrup M, Wasnich RD et al. Alendronate and

estrogen-progestin in the long-term prevention of bone loss: four-year

results from the Early Postmenopausal Intervention Cohort Study. Ann

Intern Med 1999; 131:935-942.

Ott SM. Ten years' experience with alendronate for

osteoporosis in postmenopausal women [correspondence]. N Eng J Med

2004; 350:190-191.

McClung MR, Geusens P, PD, el al. Effect of

risedronate on the risk of hip fracture in elderly women. N Eng J Med

2001; 344:333-340.

Other reference

Chan AS. Ten years' experience with alendronate for

osteoporosis in postmenopausal women [correspondence]. N Eng J Med

2004; 350:190.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org

[Guest guest]

What an appropriate name for a bone doctor. Sue

>

> However, in a response, 2 of the authors of the original report, Dr

> Henry Bone (Michigan Bone and Mineral Clinic, Detroit)

[Guest guest]

LOL, Sue!

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org

Re: [ ] Questions over Fosamax (alendronate) long-term

data

> What an appropriate name for a bone doctor. Sue

> >

> > However, in a response, 2 of the authors of the original report, Dr

> > Henry Bone (Michigan Bone and Mineral Clinic, Detroit)