First reports came in 2005
Neviaser and associates mention case reports from 2005 that described nine patients who sustained spontaneous nontraumatic, nonpathologic fractures while on prolonged alendronate therapy (>3 years).2 In 2007, Goh and colleagues reported 13 subtrochanteric fractures, nine of which occurred in patients treated with alendronate. Of the nine, eight had a pattern associated with cortical hypertrophy.3
Cause-and-effect relationship remains unproven
The proximal femoral shaft is normally subjected to high stress, Neviaser and colleagues observe, and would not be expected to fracture from minimal trauma without underlying bone pathology.
In their study, 11 patients who had untreated osteoporosis had femoral-shaft fractures, but none had this specific pattern (unicortical beak, hypertrophied diaphyseal cortex). The authors hypothesize that adynamic metabolism from impaired resorption may be the underlying pathophysiology that leads to these fractures. They also point out that, although the pattern was 98% specific to alendronate users, this does not necessarily prove cause and effect—only an association. Clearly, further study is necessary.
LATE-BREAKING NEWS: DENOSUMAB BUILDS BONE
Denosumab outperforms alendronate in phase 3 trial
Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res. 2008; Sep 3 [Epub ahead of print].
In the first head-to-head comparison of a nonbisphosphonate with alendronate, Brown and colleagues found significantly increased BMD at the total hip with denosumab after 12 months of use (3.5% vs 2.6%; p<.0001). This finding was reported at the American Society of Bone and Mineral Research annual meeting in Montreal in September.
Denosumab is an antiresorptive agent that inhibits osteoclast-mediated bone resorption and works through a different pathway than bisphosphonates. It is a fully human monoclonal antibody that neutralizes RANKL, a key mediator of osteoclast function, formation, and survival. Denosumab is injectable (subcutaneous) and is given every 6 months.
All sites showed improvement in BMD
In the phase 3 trial, 1,189 postmenopausal women who had a T-score at the total hip or lumbar spine ≤-2.0 were randomized to receive a subcutaneous injection of denosumab (60 mg every 6 months plus an oral placebo weekly) or oral alendronate (70 mg weekly plus a subcutaneous placebo injection every 6 months). Bone mineral density was monitored at various sites to detect any changes, as were bone-turnover markers at various times during the study.
In addition to BMD at the total hip, denosumab increased BMD at the following sites at 12 months, compared with alendronate:
- femoral neck, 0.6%
- trochanter, 1.0%
- lumbar spine, 1.1%
- distal radius, 0.6% (p≤.0002 at all sites).
Denosumab also was associated with a significantly greater reduction of bone-turnover markers than alendronate. The two groups had similar laboratory values and adverse events.
Although these preliminary results are extremely encouraging, we await data on fracture reduction from a study under way in postmenopausal women who have osteoporosis before definitive recommendations can be made about this agent.