The “Great Debate” at the 2019 ACR/ARP Annual Meeting addressed the issue of whether anabolic therapies are appropriate as first-line treatment for glucocorticoid-induced osteoporosis (GIO). The risk is usually defined based on previous fracture history, low T-score, and the presence of multiple risk factors for fracture including smoking, alcohol, or low body weight. Kenneth Saag, MD, presented the “pro” side while Mary Beth Humphrey, MD, PhD, presented the “con” side of using anabolic agents for GIO.

Audience members were surveyed on their opinion, with 60% of participants indicating their preference for using anabolic agents including teriparatide as first-line therapy for GIO. It was interesting to see this audience response, as certainly those advocating the use of teriparatide “won.” I was actually surprised the margin wasn’t even greater for the pro side, because clearly anabolic drugs are superior to any antiresorptive agents for fracture protection in high-risk patients, with better bone efficacy data.

The main problem is that there have been no head-to-head trials conducted with fracture reduction as a primary end point for GIO. Several trials have shown bone mineral density (BMD) differences between drugs. Dr Saag noted in his presentation that research has found statistically significantly fewer fractures in patients taking teriparatide, but again, the fracture rate was not indicated as a primary end point in the design of the clinical trial. There also may never be a head-to-head trial for various drugs in GIO, the main reason being obviously the cost of conducting such trials.

Dr Humphrey indicated that patient preference, satisfaction, and adherence should also be taken into account when debating whether anabolic agents should be given to a patient at high risk for GIO, suggesting that some patients will not elect to receive medication delivered by injection. In general, patients don’t want an injection when they can be prescribed a pill. From my point of view, the conversation should then shift to “which is the best and most effective drug given your risk factors.” From there we usually can come to a consensus that may include an anabolic agent. As for medication adherence, a patient who has a history of vertebral fracture and back pain may be more likely to be adherent than someone who is asymptomatic.

What I have found to be the larger issue, not only for payers but also patients, is the cost of the anabolic agents, especially for patients with Medicare who are dealing with the “donut hole”: those who are unable to use copay cards available to other patients with commercial insurance.

From a pathophysiologic perspective, I like to refer back to studies referenced in the past that point to the “foundational effect of an anabolic.” Researchers studied the effects of alendronate vs romosozumab in postmenopausal women with osteoporosis in the ARCH trial (Study to Determine the Efficacy and Safety of Romosozumab in the Treatment of Postmenopausal Women With Osteoporosis, ClinicalTrials.gov Identifier: NCT01631214). This trial found that patients who were treated with romosozumab for 1 year followed by alendronate had a significantly lower risk of fracture compared with patients treated with alendronate alone. The fracture rate in people who had taken romosozumab in the first year was significantly less because of the foundational effect of the drug. The process consists of laying down new bone and then consolidating that new bone formation. That is what we have always had to consider, and this speaks to Dr Humphrey’s point that you do need to continue on an oral bisphosphonate after romosozumab to consolidate the bone after treatment with an anabolic. I like to tell my patients that this process of building bone is like a spring: first you expand the spring, then you have to prevent “bounce back” to the set point.

Dr Saag mentioned that he was not advocating anabolic agents as first-line treatment for every patient; these agents should be reserved for high-risk patients. I absolutely agree with him. We do not want to give teriparatide, abaloparatide, or romosozumab to everyone. In some patients, oral bisphosphonates are perfectly appropriate.

Another point that was mentioned during the Great Debate was the risk for osteosarcoma, which was mainly derived from rat toxicology data using Fischer rats with open epiphyses their entire lives. The incidence of osteosarcoma was found to be markedly higher at baseline compared with humans. However, this osteosarcoma risk was noted by researchers; a registry was started to examine this link, and a drug length use limitation is imposed with some drugs. The registry is still insufficiently powered, so we are not yet certain that there is no relationship between the drugs and the risk for osteosarcoma. Thus far, various tumor registries in the United States have looked at the incidence of osteosarcoma with teriparatide use and no increased signal has been found.

Currently use of romosozumab is limited to 1 year because the effect tends to wane after 12 months. This is probably because the effect on osteoblasts is so potent that it depletes the osteoblast, and after a year there is nothing “left to do.” After 1 year, romosozumab becomes an expensive antiresorptive drug. What is further notable is the lack of information on the label about retreatment, as well as the lack of further guidelines about retreatment.

The current gaps in preventing glucocorticoid-induced osteoporosis are similar to those present in preventing postmenopausal osteoporosis. The number of people in whom bone density is being measured and who are being diagnosed with osteoporosis is decreasing. I think some patients may be risk averse because of the issues related to atypical femur fractures and osteonecrosis of the jaw. I think physicians may also be too busy to elevate this issue, even though mortality after hip fracture in women is 20% after one year and in men it’s 40%.

More broadly speaking apart from GIO, I believe the biggest game changer in osteoporosis research being presented is romosozumab. We now have a new anabolic agent that works differently than teriparatide as a signaling pathway drug. STUCTURE (An Open-label Study to Evaluate the Effect of Treatment With Romosozumab or Teriparatide in Postmenopausal Women; ClinicalTrials.gov Identifier: NCT01796301) studied the effect of 1 year of treatment with romosozumab compared with teriparatide on total hip BMD in postmenopausal women with osteoporosis who were previously treated with bisphosphonate therapy. The investigators found a dramatic increase in BMD with romosozumab therapy compared with teriparatide. Importantly, they also conducted finite element analysis at the hip that showed increased hip strength with romosozumab. Given these data, I believe this is the biggest story right now in osteoporosis.

Disclosure: Dr Deal is a speaker and consultant for Radius and Amgen.