TO THE EDITOR: This drug review deserves a response. Safety data for denosumab (Prolia) are available from studies with five years of follow-up (an international, randomized, double-blind, placebo-controlled phase 3 trial1,2) and six years of follow-up (a phase 2 extension study3). Overall, there was no difference in the rate of infections between the treatment and placebo groups during the first three years of the trial, although serious adverse events of cellulitis were more common in the treatment group (4.1 versus 3.4 percent). However, in the phase 2 extension study, the rate of serious infections in years 4 through 6 was similar to that in the placebo group in years 1 through 3 (1.3 per 100 subject-years).
In addition to meeting the primary end point of reduced vertebral fractures at three years, study participants who received denosumab had a 61 percent reduction in their risk of vertebral fracture at one year, and a persistent reduction of vertebral fractures through five years (1.1 percent incidence).1,2
The price of denosumab varies. One must consider the issue of compliance with therapy and the medical costs that occur because of nonadherence to a prescribed regimen (including treatment of fractures). A longitudinal cohort study of osteoporosis therapy showed that patients who reported greater satisfaction with treatment were more likely to continue osteoporosis therapy.4 The 24-month Denosumab Adherence Preference Satisfaction randomized crossover study reported that 92 percent of women preferred denosumab to alendronate (Fosamax), and that 93 percent of participants receiving denosumab were compliant with treatment for one year, compared with 63 percent of those receiving alendronate.5
The article notes that denosumab can be used in patients with renal impairment. Women who are at highest risk of hip fractures—those 80 years and older who have osteoporosis—have a 54 percent incidence of severe renal compromise (creatinine clearance less than 35 mL per minute per 1.73 m2 [0.58 mL per second per m2]).5
Consistent with the American Association of Clinical Endocrinologists guideline,6 I suggest that denosumab is an appropriate first-line choice for the treatment of postmenopausal osteoporosis, especially in women with impaired renal function.
IN REPLY: I appreciate Dr. Simonelli's comments regarding the drug review on denosumab for postmenopausal osteoporosis. The longest-term safety data available are from the use of denosumab in approximately 80 patients for a total of eight years in a phase 2 extension study.1 Other long-term data are from use in approximately 2,000 patients for a total of six years.2 The data from both of these studies showed continued increases in bone mineral density and a continued low incidence of vertebral and nonvertebral fractures.1,2 Although it is reassuring that the incidence of serious adverse effects, such as infections and malignancies, did not increase with continued exposure to denosumab, these effects were consistently reported. The overall incidence of infection was similar between the denosumab and placebo groups, but the treatment group had more serious infections that required hospitalization, as well as endocarditis and skin, abdominal, urinary tract, and ear infections.3 Additionally, four cases of osteonecrosis of the jaw were reported in the extension study.2 Although this type of information is needed to determine the long-term effectiveness and safety of denosumab, it should be interpreted with caution. Rare but serious events need to be carefully followed because they may become more common with widespread use in a more heterogeneous population.
I do not find it surprising that the study referenced by Dr. Simonelli found better compliance with denosumab compared with the once-weekly oral bisphosphonate alendronate.4 Annual intravenous zoledronic acid (Reclast) would have been a better comparison.
Renal impairment is not listed as a contraindication to denosumab use and no dose adjustment is required in patients with renal impairment. However, patients with creatinine clearance of 50 mL per minute per 1.73 m2 (0.83 mL per second per m2) or less have an increased risk of developing hypocalcemia.5 Most bisphosphonates are not recommended in patients with creatinine clearance of less than 35 mL per minute per 1.73 m2 because of limited data in this population. A recent study that examined the relationship between denosumab use and degree of renal impairment found that renal impairment was not associated with a decrease in effectiveness or an increase in adverse effects.6 However, most patients in this analysis had an estimated glomerular filtration rate of at least 30 mL per minute per 1.73 m2; only 73 of the 4,069 patients had an estimated glomerular filtration rate of 15 to 29 mL per minute per 1.73 m2; and no patients had stage 5 chronic kidney disease.6