Tag Archive for: denosumab

The next big new bone building drug has hit your doctor’s office. Impressive claims that the drug reduces fractures by 73% are being tossed around. But bisphosphonates were once touted in similar terms and are falling out of favor due to side effects and limited efficacy.

Do the stats in these studies mean anything real?

Whenever I research any new bone building drugs, I look at the research and ask a set of key questions to see whether there is any good news. I’m sharing them with you so you have tools to help you assess what you hear.

5 questions to ask when evaluating bone building drugs

Question #1: What’s the nature and action of the drug? What will its long-term effects be?

The experimental bone drug I mentioned is a monoclonal antibody called romosozumab that inhibits action of a protein in the body known as sclerostin. Some time ago, it was discovered that sclerostin deficiency causes a rare genetic disorder characterized by high bone mass and resistance to fracture, so the pharmaceutical industry decided to make a drug to block this protein and see if it could reduce bone breakdown and enhance bone buildup.

Now Romosozumab is a drug that tinkers with both bone breakdown and bone formation in a whole new way, and its discoverers claim that “the risk of new vertebral fracture was 73% lower in those who took the drug.” Pretty impressive, if it’s true. So let’s take a closer look and continue asking questions.

To begin with, an important unanswered question is, “What are the many roles that sclerostin plays in the body, and what will be the long-term impact of suppressing this protein?” The current study does not address the issue of long-term impact or safety, and it often takes 10+ years to see the full effects of such tinkering with human physiology. For now, we know roughly how the drug acts, but we do not know what its long-term effects are.

Question #2: How many people participated in the study, and how were they selected?

This study looked at 7180 postmenopausal women ages 55 to 90 with a hip bone density T score between -2.5 and -3.5. The group was divided into two subgroups — 3325 who took the drug, 3327 who were given a placebo. So on the surface, this is a strong study — it includes a large sample of individuals who are similar in age, gender, and baseline bone density, and the groups are equivalent in size.

But a closer look shows that those at higher risk of fracture were excluded from the study. That includes women with a hip T score worse than -3.5, a history of hip fracture, or even one severe or more than two moderate vertebral fractures; those with a vitamin D below 20 ng; women with high or low blood or calcium as well as those with bone diseases or conditions affecting bone metabolism.

In other words, they chose participants based on low bone density rather than fracture risk (and if you’ve read my blogs, you know that the two aren’t necessarily the same).

Question #3: How long was the study?

Study subjects were only given the new drug, romosozumab, for 12 months and then switched to another monoclonal antibody bone drug, denosumab (Prolia^®), in the second year. While researchers do not explain why they switched to another drug, I suspect they feared extended use of this new drug would result in serious longer-term adverse effects. This is not unlike the case with the drug teriparatide (Forteo^®), the use of which is limited to two years due to potential life-threatening impacts.

Question #4: What is the real-life fracture-reduction benefit?

The length of the study is important because the short-term fracture reduction benefits may be very different from the long-term ones. In this case, all we have is a 1-year study with romosozumab and then another year-long study switching all study subjects (those on placebo and those on romosozumab) to the denosumab (Prolia^®) bone drug. This makes the study a little confusing, but I’ll try to clarify the findings:

• Only a few vertebral fractures were prevented by using either of the two drugs. The study had a total of 6,652 women, all of whom had a pretty low fracture risk to begin with. In the first year of the study using romosozumab versus placebo more than twice as many women (59) in the placebo group experienced vertebral fractures than the women in the romosozumab group (16). So when you look at how many women were spared from a vertebral fracture by taking the new drug (that is, 59 – 16 = 43 women), you realize that for every 1 woman who benefited, there were 76 others in the drug group who took the medication and got nothing out of it. If your doctor told you he had to treat 3,327 women to prevent just 43 vertebral fractures, you might look into other ways to strengthen your spine.
• Both drugs put together had very little benefit on vertebral fracture. Among the 3,327 women who received placebo the first year and then were put on denosumab in the second year, there were 84 new vertebral fractures, whereas the women who took romosozumab the first year had only 21. Overall, then, 63 women out of 6652 were saved from having a fracture by taking bone drugs for both years. That’s not even 1% of the total number of participants.
• The new drug had almost no impact on non-vertebral fractures. Vertebral fractures often cause no symptoms in those who have them, but others — like fractures in the wrist, collar, arm or hip — can be more serious and painful. Such fractures occurred in 56 patients on the new drug and 75 in the placebo group. That means the drug helped prevent only 19 of the 3,327 women avoid non-vertebral fractures with over 1 year of treatment. So you’d have to treat 175 women to save just 1 woman from fracturing a hip. And when you take the second year into account, when all the participants took bone drugs, you find no significant difference in risk between the romosozumab group and the placebo group. So if you were looking to prevent fractures of the hip, wrist, collarbone, arm, or other non-vertebral fracture, the new drug was no help at all.

Question #5: What are the reported and potential adverse effects of the drugs?

In this 1-year trial of romosozumab, adverse effects included the following: hypersensitivity to the injection; 2 cases of osteonecrosis of the jaw; 1 atypical femur fracture; a high incidence of anti-romosozumab antibodies (the impact of this on the immune system is yet unknown); and lowered serum calcium levels in those using romosozumab. These are all fairly serious problems.

Is there a better way to reduce needless fractures?

From my nearly 3 decades of clinical practice and bone health research, I confidently say yes, there is a better way! And that better way is one that builds Better Bones and a Better Body naturally, without the many risks of bone drugs.

Approaches like my Better Bones Program enhance health, vitality, and fitness while reducing fracture risk. Why not take a few minutes to review the steps to the Better Bones, Better Body Program and get started strengthening your bones today?

Reference:
Cosman, Felicia et al., Romosozumab treatment in postmenopausal women with osteoporosis. New England Journal of Medicine 2016;375:1532-1543.