Denosumab versus alendronate
Brown and associates compared denosumab and alendronate in a randomized, blinded trial of 1,189 postmenopausal women who had a T-score worse than –2.0 at the lumbar spine or total hip. At month 12, denosumab significantly increased BMD at the total hip, compared with alendronate (3.5% versus 2.6%) (P < .0001). Compared with alendronate, denosumab also increased BMD in the:
- femoral neck (0.6%)
- trochanter (1.0%)
- lumbar spine (1.1%)
- 1/3 radius (0.6%) (P ≤ .0002 for all sites).
Denosumab led to significantly greater reduction of bone turnover markers than did alendronate therapy. Unlike bisphosphonates, denosumab is not retained in bone.
Participants were randomized 1:1 to:
- 60 mg subcutaneous denosumab injection every 6 months plus oral placebo weekly (n=594)
- 70 mg of oral alendronate weekly plus subcutaneous placebo injections every 6 months (n=595).
BMD was assessed at 6 and 12 months, and bone turnover markers were assessed at 1, 3, 6, 9, and 12 months. Safety was evaluated by monitoring adverse events and laboratory values.
No significant difference between denosumab and alendronate was observed in the overall incidence of adverse events (80.9% versus 82.3%, respectively) (P =.60), including gastrointestinal disorders, infections, and neoplasms. Most adverse events were mild or moderate in severity. Treatment-related adverse events were similar between groups (17% and 18.3% for denosumab and alendronate, respectively). Similar numbers of women experienced serious adverse events (34 women [5.7%] taking denosumab versus 37 [6.3%] taking alendronate). The overall safety profile was similar for both drugs.
Is osteonecrosis of the jaw a concern with denosumab?
The package insert for Prolia mentions that osteonecrosis of the jaw (ONJ) can “occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing and has been reported in patients receiving Prolia.”
Although no cases of ONJ were reported in the FREEDOM trial, a letter by Kyrgidis and Toolis to Osteoporosis International makes the point that ONJ may not be related solely to bisphosphonate use.1 Taylor and colleagues described a case of a cancer patient who had never taken a bisphosphonate but who was treated with denosumab and later developed ONJ.2 Kyrgidis and Toolis refer to presentations in the European Journal of Cancer Supplements that reported on head-to-head trials of denosumab and intravenous zoledronic acid in the treatment of bone metastases in cancer patients.1 In one trial, the incidence of ONJ with denosumab was 2.0%, compared with 1.4% for zoledronic acid (P =.31). In another trial, the incidence of ONJ was 1.1% for denosumab and 1.3% for zoledronic acid (P =1.0). Kyrgidis and Toolis concluded that the association between ONJ and denosumab appears to be somewhat dose-related, as it is with bisphosphonate-related ONJ.
Plausible mechanisms for denosumab-related and bisphosphonate-related ONJ include defective osteoclast differentiation, function, survival, and “fatigue.”
Because denosumab has a shorter clearance time than bisphosphonates do, it seems feasible that treatment of denosumab-related ONJ will be easier and healing earlier than with bisphosphonate-related ONJ.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
Denosumab is a highly effective, safe treatment for patients who have osteoporosis and who are at high risk for fracture. Its twice-yearly administration can significantly enhance compliance, compared with drugs that are taken orally either weekly or monthly. While the drug may appear to be expensive, its cost should be “amortized” over 6 months, rendering its expense roughly equivalent to that of daily, weekly, or monthly products.
Although denosumab is injectable, it is an effective first-line drug for patients who have a high risk of fracture.
Osteonecrosis of the jaw in bisphosphonate users
Otto S, Abu-Id MH, Fedele S, et al. Osteoporosis and bisphosphonates-related osteonecrosis of the jaw: Not just a sporadic coincidence—a multi-centre study [published online ahead of print June 25, 2010]. J Craniomaxillofac Surg. doi:10.1016/j.jcms.2010.05.009.
ONJ is a serious side effect well known to practitioners of maxillofacial surgery.3 Most research into the condition has focused on patients who have bone metastasis who have received intravenous bisphosphonates. In this report, Otto and colleagues describe a large multicenter trial at 11 European centers from 2004 through 2008. ONJ occurred in 470 patients taking a bisphosphonate. Each case was clinically examined, and a detailed history was supplied.
Although more than 90% of these cases were associated with intravenous bisphosphonate use, mainly in cancer patients who had bony metastasis, 37 cases (7.8%) occurred in women taking an oral bisphosphonate for osteoporosis. Of these, only 43% had any of the risk factors defined by the American Association of Oral and Maxillofacial Surgery (such as duration of bisphosphonate use and previous dental procedures). That means that 57% of these cases would be considered low-risk.