Actonel Risedronate
Actonel is a member of the bisphosphonate family and is a very effective treatment for osteoporosis. My clinical experience with the drug suggests that it is better tolerated than alendronate and as or more effective especially for hip fracture rate reduction. Ironically, Actonel did not get the hip fracture indication from the US FDA because of a critical error made by the study management team in an attempt to reign in the cost of the study.

Indications and Usage for Actonel from the Label
Postmenopausal Women:
Actonel is indicated for the treatment and prevention of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, Actonel reduces the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures.

Osteoporosis in Men:
Actonel is indicated for treatment to increase bone mass in men with osteoporosis.

Glucocorticoid-Induced Osteoporosis:
Actonel is indicated for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage of greater than or equal to 7.5 mg of prednisone or equivalent) for chronic diseases. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.

Paget’s Disease:
Actonel is indicated for treatment of Paget’s disease of bone in men and women.

Treatment of Osteoporosis in Postmenopausal Women
The fracture efficacy of Actonel for vertebral and peripheral fractures was studied in 2 trials one of 1374 postmenopausal women in North America and the other 690 in Europe and Australia. All subjects took calcium and vitamin D. The subjects were selected to be in the study if they were postmenopausal women with at least one vertebral fracture. The North American group had 2 fractures each on average while the Europe/Australian women had 4 fractures on average.

At the end of the 3-year study of the North American women, the fracture rate was a statistically significant 185 per 1,000 in the placebo vs. 139 per 1,000 in the treatment group arm for a relative risk reduction of 33%. The absolute risk reduction was 4.6% translating into the need to treat 22 women like those in the study for 3 years to prevent 1 new vertebral fracture.

The peripheral fracture rate was 80 per 1,000 the placebo group vs. 50 per 1,000 in the Actonel group for a statistically significant relative risk reduction of 39% and an absolute risk reduction of 3%. To prevent 1 new peripheral fracture in women like those in the study would require treatment of 30 subjects for 3 years.

In the Europe/Australia group, the rate on new vertebral fractures was 340 per 1,000 in the placebo group vs. 218 per 1,000 vs. per 1,000 in the placebo group for a statistically significant relative risk reduction of 46%. The absolute risk reduction was 12.2% meaning that in women like these a new vertebral fracture was prevented for every 8 subjects placed on Actonel.

The peripheral fracture rate was 160 per 1,000 in the placebo group and 110 per 1,000 in the Actonel group for an absolute risk reduction of 5%, which was statistically significant and meant that 1 new peripheral fracture will be prevented when Actonel is prescribed to 20 women like those in the study for 3 years.

The bone density increased about 5% in the spine, 1.5% at the femoral neck, and 3.5% in the total hip in the Actonel treated subjects over the 3 years of treatment, which was statistically significant compared to the change from baseline and with the change in the placebo group.

This is the second study where we saw the effect of previous fractures on the risk for subsequent fracture. The first was in the Fosamax FIT study. This study clearly illustrated the point and Dr. Nelson Watts etal wrote a defining paper about this based upon this and the data from other osteoporosis studies including the FIT study data that raised the entire clinical communities awareness of how important this finding was. It is also interesting to note that it did not make any difference if the patient was aware of the fracture or not, the presence of one fracture predicted the second. The more fractures the patient had the, the higher her risk for future fractures. The last piece of intelligence that came from this data was the grade of the fracture matters. Fractures are graded 0 through 3 with 0 being no fracture and 3 being a completely crushed vertebra flat as a pancake. The higher the fracture grade, the higher the risk for another fracture would happen.

In a post hoc pooled analysis of hip fracture risk of a group of 5445 women between the age of 70 and 79 with T-scores <-3 two doses of Actonel were compared with placebo in a 3 years study. All subjects took calcium and vitamin D. The hip fracture rate in the placebo group was 32 per 1,000 vs. 19 per 1,000 in the Actonel subjects resulting in a statistically significant 40% relative risk reduction in hip fracture. The absolute risk reduction was 1.3% meaning 77 women like those in the study would need to be treated for 3 years to prevent 1 new hip fracture.

The US FDA did not permit the company to promote this hip fracture data because of an unplanned change in the study design in the middle of the ongoing study despite these results being the best (P=0.009) seen for any drug ever tested for hip fracture reduction. The study manager decided to discontinue the lower of the two dose of Actonel being tested for osteoporosis treatment because “surely that is the rationale approach” to cutting costs and still getting data useful for drug approval and marketing. At the conclusion of the study, everyone was astonished to discover the statistically significant rate reduction for hip fracture was only seen in the low dose group that was terminated. What is even more interesting is that those benefits occurred after an average of only 18 months to treatment.

The bone density increased about 5% in the spine, 1.5% at the femoral neck, and 3.5% in the total hip in the Actonel treated subjects over the 3 years of treatment, which was statistically significant compared to the change from baseline and with the change in the placebo group.

Initially I thought this was a weakness of Actonel because when this study was conducted in the early 1990s the dominate thinking was the greater the increase in bone density the more potent the fracture preventing effect of the drug. This data was clearly pointed in a new direction because Actonel therapy resulted in robust fracture rate reductions without affecting DXA bone density in the same proportion as Fosamax for instance. At the time, this remained a conundrum. Later the mechanism of action of bisphosphonates began to be understood better and the effect this had on bone quality. A greater appreciation of the how important bone remodeling is to skeletal health and fitness. It became apparent that prolonged use of drugs that continually suppressed bone remodeling resulted in accumulation of dead bone. This effete bone underwent, uncontrolled progressive mineralization that ultimately caused it to become brittle and fracture prone. This insight has had a far-reaching effect on my views of how to prevent and treatment of osteoporosis.

Important Limitations of Use
The optimal duration of use has not been determined. The safety and effectiveness of Actonel for the treatment of osteoporosis are based on clinical data of three years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

Warning
Renal Impairment:

  • Actonel is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min).

I agree with this warning. Prolia is a better choice here.

Warning
Atypical Subtrochanteric and Diaphyseal Femoral Fractures:

  • Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. This does happen but mainly with Fosamax treated patients.

I have never seen it in an Actonel treated patient before. There are probably some cases reported in the literature. Most of these cases are related to Fosamax for unknown reasons.

Warning
Jaw Osteonecrosis

  • Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including Actonel.

This is a rare event with Actonel in my opinion and not a reason to avoid this or any osteoporosis drug despite the concern that some express about it. It almost never happens.

Warnings
Upper Gastrointestinal Adverse Reactions

  • Actonel, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Actonel should be avoided in patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers)
  • Esophageal adverse experiences, such as esophagitis, esophageal ulcers, and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates.

The irony here as with Fosamax is that in the research studies of Actonel the subjects did not complain of stomach upset or indigestion any more often than those on placebo. I think Actonel causes upset stomach in patients but less than Fosamax does.