In April 2019, the FDA approved romosozumab (Evenity), a new osteoporosis drug targeted at postmenopausal women with high risk for fracture. I looked at the data used by the FDA in granting approval for the drug — and it’s far from confirming the runaway success of Evenity that Big Pharma would lead us to believe. So before you fill that prescription, here’s some information I think you should know.
Evenity is a monoclonal antibody that suppresses a protein called sclerostin, which also regulates bone formation. In people who have a rare genetic disorder called sclerosteosis, sclerostin is very low, which allows osteoblasts to build bone at will. People who are born with sclerosteosis or a milder form called Van Buchem Disease have enhanced bone formation and denser, stronger bones than average — typically, Z-scores in the spine of as much as +7.7–+14.4. This might sound great to someone with osteoporosis, but the truth is, unimpeded bone building with nothing stopping it eventually causes serious harm, including entrapped nerves and enlargement of the skull, which puts pressure on the brain — and most people with sclerosteosis don’t live past their 30s.
Knowing this, researchers looked for a way to inhibit sclerostin in women with low bone mass to see if it would cause them to develop greater bone density. And it does — although this shouldn’t surprise anyone. The principle of “use the body’s own mechanisms to build bone” is a fairly sound idea on the face of it. Where it runs into problems — and Evenity is no exception — is when you put normal bodily mechanisms on overdrive, as most of these medications do.
The data used for the drug’s approval comes from two trials: The FRAME study (FRActure study in postmenopausal woMen with ostEoporosis) and the ARCH study, both of which looked at postmenopausal women at high risk for fracture.
The FRAME study enrolled 7180 postmenopausal women with a T-score of –2.5 to –3.5 at the total hip or femoral neck — so, definitely in the bone loss zone that defines osteoporosis. Half of these women were given Evenity, while the other half got a placebo. All of the participants also got at least 500 mg calcium and 600 international units (IU) of vitamin D supplementation daily, and anyone in either group who had serum 25-hydroxyvitamin D concentrations of 40 ng/mL or less (which was a whopping 77% of participants!) was given a loading dose of 50,000 to 60,000 international units of vitamin D within one week of randomization. After 12 months on Evenity, all of the participants were switch to Prolia for 12 months.
The ARCH study was similar, except instead of following the year of Evenity or placebo with a year of Prolia, participants received alendronate (Fosamax). And as in the other study, the 4093 participants were all given 500 mg of calcium and 600 IU of vitamin D, and 74% had the same vitamin D loading dose as in the FRAME study.
So, how did the patients taking the drug fare? When you read the FRAME researchers’ publication in the Journal of Bone & Mineral Research, the numbers are staggering: “after 12 months of romosozumab, at the lumbar spine, 96% of patients achieved gains ≥3% from baseline, 89% of patients achieved gains ≥6%, and 68% of patients achieved gains ≥10%, compared with 22%, 6%, and 1% of patients receiving placebo” — amazing numbers!
Are they too good to be true? You bet they are.
Let’s go back for a minute and consider the protocols used in the FRAME and ARCH studies. Each of the women enrolled had osteoporosis — it was a prerequisite for participating. All of them got vitamin D tested, and well over two-thirds in both studies were identified as being deficient and given a therapeutic dose of vitamin D. (It’s also interesting to see that the cutoff point for vitamin D deficit was set at 40 ng/mL, higher than the usual 30 ng/mL).
While the results from the drug arm of the FRAME study are astonishing, what’s really interesting are the results from the placebo group in the FRAME study, where 29% of the participants had a 3–10% improvement in bone density just from the added vitamin D and calcium. Meanwhile, 47% had a decrease in bone density. The remainder (24%) saw no significant change.
What this means is that the vitamin D therapy alone enabled more than half (53%) of the women in the placebo group to halt their bone loss and, for some, start building bone. It’s problematic for the findings because this “placebo” arm did not actually use a placebo — what it did was identify a common cause of bone loss and treat it using nutrition (sound familiar?). How much more improvement would this groups have seen if they had also used weight-bearing exercise and the remaining key nutrients as part of its “placebo”?
The findings from the FRAME trial’s placebo arm also imply something else: that nearly 2000 of the women who were given Evenity could have halted their bone loss and perhaps started to build bone even without the drug, just by improving their vitamin D status.
However, they built even more bone with the drug, and that’s good, right? Well, if that were all the drug did, it certainly would be. But the bone drug Evenity comes with a black box warning of increased risk of heart attack, stroke, and death. One has to wonder if the risk of a heart attack is really worth it for the thousands of women who took this drug without realizing that the “supportive” treatment — vitamin D therapy — might be responsible for at least some of the bone-building effects.
The news from the ARCH trial is no different: It found reductions in fracture incidence (which you’d expect) but increased cardiovascular events, as well as a few instances of the atypical fractures and osteonecrosis of the jaw — problems that have been associated with bisphosphonates in the past.
Not to mention, the reason these studies were constructed with only 1 year of Evenity followed by 1 year of a different drug is that Evenity stops working after 1 year. It’s a pity that the researchers didn’t follow a year of Evenity with a year of just nutritional support to see whether the gains seen in the women who took the bone drug Evenity were maintained. (Maybe they didn’t want to know the answer…)
Lewiecki EM. Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone disease. Ther Adv Musculoskelet Dis 2014;6(2):48-57.
Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017 Oct 12;377(15):1417-1427.
Sancar F. Caution with new osteoporosis drug. JAMA 2019;321(19):1862.