Consider the Bisphosphonate Dose

Zoledronate 5 mg/year significantly reduces the risk of fractures, but is this the optimal dosing regimen? We should consider whether other doses would be safer or more effective, whether long-term effects would continue to show benefits, and whether different doses should be used in diverse physiological conditions. Excess bone remodeling can lead to a higher percentage of weak immature bone with lowmineralization. High bone resorption is also harmful because resorption cavities are stress risers, impairing the structural integrity of a trabecula of bone. Furthermore, there is increased likelihood that cavities will occur on both sides of a trabecula, causing perforation and loss of structural elements. As Parfitt noted, when resorption is blocked, the risk of buckling falls within a few weeks, before there has been any measurable increase in bone mass, so only a small effective dose of an antiresorptive agent may be sufficient to abrogate the mechanical threat. The dose-effect of risedronate was studied in a trial of 5445 women with osteoporosis randomized to treatment with placebo, 2.5 mg/day, or 5 mg/day. The rate of hip fracture compared to placebo was significantly decreased with the 2.5 mg dose but the decrease with the 5 mg dose was not significant, even though bone density was higher with the higher dose. The higher dose was marketed, in a decision that prioritized a surrogate result over a patient-centered outcome. If bone density were the only consideration, then fluoride would be the best drug because it increased spine bone density by 35% in a 4-year trial that demonstrated a greater rate of fractures compared to placebo. The initial dose-finding study of alendronate compared 5, 10, 20 and 40 mg/day. After a year the increase in spine bone density was highest for 20 mg, but lowest for 40 mg. By 2 years the 5 and 10 mg/d groups had the same increase in bone density. A larger study compared doses and found greater changes in bone mineral density (BMD) with 10 mg than 5 mg, but the vertebral fracture risk was the same (2.9% and 2.8%). The alendronate fracture intervention trial in women with vertebral fractures used a dose of 5 mg/day for the first 2 years, then switched to 10 mg/day for the last year. This was not actually a dose comparison, but it is worth noting that the significant benefit on fracture rates was already seen during the first 2 years, and within the treated group the fracture rates for hip or spine were higher in the third year (with the higher dose) than the second year. Due to coupling, the bone formation rate is reduced in proportion to the reduction in resorption. Currently prescribed doses of bisphosphonates strongly inhibit bone formation by 90%. Bone turnover is a normal physiological process that prevents excessive aging of bone and repairs microscopic damage. The mean lifespan of bone in the normal ilium is 13 years in cortical bone and 5.6 years in cancellous bone, so the effects of this severe reduction in bone formation are not obvious during the first few years. However, bone can no longer repair damage because bone resorption is necessary to remove the damaged area. Bone also slowly becomes hypermineralized. Overall the bone from patients with long-term bisphosphonate use is older, more densely mineralized, and has abnormal spectroscopic measurements. The optimal duration of bisphosphonates use has been debated. A randomized trial of continuing alendronate beyond 5 years showed no difference in the rate of all clinical fractures between those continuing the drug and those on placebo for the subsequent 5 years, even in the subset with osteoporosis (T-score < 2.5). Likewise, the rate of clinical fractures was not significantly different in those who had taken zoledronate for 3 years and were randomized into further medicine or placebo for 3 years. Epidemiological studies have shown increased risk of atypical femur fractures in patients using bisphosphonates longer than 5 years. These fractures have not been observed in women with prolonged use of estrogen, which reduces osteoporotic fractures and moderately reduces bone resorption, or in persons who have prolonged use of thiazide, which mildly reduce bone resorption and is associated with 24% lower rates of hip fracture compared to nonusers. It is theoretically possible that low bisphosphonate doses could be used for decades without causing atypical fractures. Too little attention is paid to the diversity of bone turnover in patients with osteoporosis. It makes physiological sense to treat patients who have excess resorption with a medication that blocks resorption. However, in those whose osteoporosis is characterized by low bone turnover, these medications are unlikely to be beneficial. This has been suggested by a post hoc study of the alendronate fracture intervention trial, in which the relative risk of fractures was analyzed according to tertiles of baseline bone turnover. Those in the lowest two tertiles did not show any significant reduction in the fracture rate, whereas those in the highest tertile showed a highly significant reduction (relative risk 0.54; 95% confidence interval [CI], 0.39–0.74). Whether low doses of bisphosphonates would reduce fractures in those with mild to moderately high bone resorption has not been studied. In patients with low bone turnover, however, it makes physiologic sense to treat with anabolic medications. Teriparatide, abaloparatide, and romosozumab are not as effective in patients previously treated with current doses of bisphosphonates. This must be taken into consideration when deciding which medications to use to prevent fractures.