Recently, Sarah came to my office reporting that her doctor wanted her to take the bone drug raloxifene (Evista™). She wanted to know if I thought this medication would benefit her, so I sat down to take a fresh look at the first and largest controlled study on this drug.
The short version of what I discovered: there is limited benefit and substantial risks with this bone drug. But to understand why, you need to know the long version: what this drug does, and what it doesn’t do.
What is raloxifene (Evista™)?
Raloxifene is a “selective estrogen receptor modulator (SERM),” which puts it in the same family as the breast cancer drug tamoxifen (it was studied for breast cancer, but proved less effective than tamoxifen). SERMs bind to estrogen receptors and mimic estrogen’s effects; the idea is that you can get estrogen’s beneficial impacts on bone, but without the negative estrogen effects of on the uterus endometrial and breast tissue.
What raloxifene’s fracture prevention trial reveals
Back in the late 1990s, researchers conducted the first (and largest) placebo-controlled fracture prevention trial to determine what raloxifene might offer for osteoporosis. This trial involved 6,828 postmenopausal women divided into two treatment groups: One that was given a placebo, and the other given raloxifene in either 60 or 120 mg daily doses.
All of the study subjects had osteoporosis as determined by bone density measurement (–2.5 T score), and some of the women had already experienced a spinal fracture. The study was three years in duration.
Fracture reduction at three years:
- Of the 6,828 women in the study, 503 (7.4%) experienced at least one new vertebral fracture during the study period.
- In the placebo group, 10.1% experienced a vertebral fracture visible on x-ray (not necessarily symptomatic) during on the 3-year study.
- In the treatment group using 60-mg doses of raloxifene, 6.6% experienced a new vertebral fracture. This represents an absolute risk reduction of 3.5% — that is, among those using raloxifene, 3.5 fewer vertebral fractures occurred per 100 women as compared to those not taking the drug.
- Importantly, there was no significant reduction in hip fracture or other non-vertebral fractures with the use of raloxifene. While spinal fractures are a key warning sign for osteoporosis, they don’t affect quality of life nearly as much as hip fractures do.
All in all, this very large study showed that this drug had a small effect on reducing vertebral fractures and no significant effect on reducing hip or other non-vertebral fractures.
The risks of raloxifine lead to FDA black box warning
Unfortunately, even this very first study on raloxifene reported serious adverse effects, most notably a three-fold increase in the risk of potentially life-threatening venous blood clots (thrombosis).
Ten years after the drug was approved, the FDA issued a black box warning about this side effect — which is the most serious notification of potentially life-threatening adverse effects the FDA can require, short of withdrawing the drug from the market. I’ve reproduced it here so you can see what it says.
Is there a better way?
After looking at this information and comparing the mild possible benefits to the significant potential harms, Sarah and I have to ask the question: Is there a better way?
Currently, there are number of bone drugs prescribed to intervene with the mechanisms of skeletal weakening, and many more are in the pipeline. Given that up to half of the women 50+ in this country will be told to take a bone drug at some point, it’s a great idea to take a look at what these drugs do, the degree to which they really prevent fracture, and their potential risks, and what other avenues might be available to you.
Then make up your own mind.
Cranney A, Adachi JD. Benefit-risk assessment of raloxifene in postmenopausal osteoporosis. Drug Saf. 2005;28(8):721-30.
Duvernoy CS1, Yeo AA, Wong M, Cox DA, Kim HM. Antiplatelet therapy use and the risk of venous thromboembolic events in the Raloxifene Use for the Heart (RUTH) trial. J Womens Health (Larchmt). 2010 Aug;19(8):1459-65. doi: 10.1089/jwh.2009.1687.
Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282(7):637-645.
So many people have asked me recently about the ketogenic “keto” diet and the benefits — and the drawbacks — of severe carbohydrate restriction.
Is the keto diet the “magic pill” for ending weight and health struggles, as a certain Netflix documentary would like us to believe? As you’ll see, absolutely not. What’s more, keto diets can actually be quite harmful to your health.
What happens in your body when you’re on a ketogenic diet
A ketogenic diet is one that limits carbohydrate intake to the point at which the “starvation response” is triggered in the body. This starvation response mobilizes stored fat and breaks it down as a way to produce acetyl coenzyme A (CoA) — the body’s backup energy source in place of the glucose it isn’t getting when we don’t or can’t eat carbohydrates.
Most standard keto diets pair the low carbs with high fat and moderate protein intake, but when weight loss is the goal, there’s often a limit on fat intake as well to encourage reduced calorie intake (since fatty foods are typically higher in calories too).
The benefits of ketogenic diets
Keto diets do have legitimate benefits when it comes to weight loss, but as you’ll see below, the risks may outweigh the benefits.
Short-term weight loss. Reducing carbohydrate intake and monitoring caloric intake will offer the body only one place to turn for energy: body fat stores. A strict ketogenic regimen can produce steady and reliable weight loss in most otherwise healthy overweight adults in the course of a few months. (I’ll get to the “but…” in a moment.)
Short-term improvement in blood sugar. Individuals who eat a standard diet who do not have diabetes, prediabetes, or insulin resistance tend to have blood glucose levels in the range of 80–120 mg/dL. Those on a ketogenic diet, however, typically have blood glucose levels between 65–80 mg/dL. Before you say, “holy hypoglycemia!” keep in mind that the body adjusts to these levels in part by producing more CoA. So for someone who might be on the borderline of diabetes and wants to better manage blood sugar levels, a keto diet can be a good place to start — although there’s a “but…” associated with this as well!
When keto diets become harmful to your health
While we evolved to use glucose as our primary energy source, our ancestors couldn’t always rely on carbohydrate-rich plant foods being available all the time. So the ability to use fats as a source of glucose (whether from animal foods they ate or by burning their own adipose tissue during times of famine) was an effective short-term backup plan. The operative phrase is “short-term.”
Because there are definitely harmful long-term effects of ketones in the body:
Keto diets acidify the body. Ketosis, which is the name for production of ketones in general, and its more dangerous, dysfunctional variant ketoacidosis (a life-threatening buildup of ketones that happens most often in diabetic individuals) results in lower blood pH — in other words, acidosis.
I’ve talked before about how acid-forming foods can be harmful to bones, but chronic low-grade acidosis has health impacts well beyond bone health. It can potentially increase risk of cancer development and progression; increases production of the stress hormone cortisol; and potentially causes the development of kidney disorders such as kidney stones (Robey, 2012; Pizzorno, 2015).
Keto diets can promote fatty liver disease and insulin resistance. This is where those two “but…” caveats from earlier come in… There is evidence in mice — and to a lesser extent in humans — that long-term use of keto diets promotes development of nonalcoholic fatty liver disease and (paradoxically) insulin resistance (Schugar & Crawford, 2012; Ellenbroek et al., 2014). The increase in insulin resistance is likely related to longer-term increases in cortisol.
So, while the short-term benefit for blood sugar and other cardiovascular makers exists with keto diets, in the long term, regulating blood sugar and other aspects of cardio health is better achieved through a balanced diet paired with regular exercise.
Keto diets are NOT the best choice for long-term weight loss
Although a keto diet may be a good starting point for shaving off pounds, it probably isn’t something you want to stick with over time — more than, say, a few months — especially if you have a family history or personal tendency toward diabetes, insulin resistance, kidney dysfunction or fatty liver disease.
This includes finding ways to gradually include a healthier set of carbs into your food choices. My favorites are nutrient-rich, alkalizing starchy vegetables like root vegetables and squash, which are full of complex carbohydrates, rather than the standards of bread and sweets.
Ellenbroek JH, van Dijck L, Tons HA, Rabelink TJ, Carlotti F, Ballieux BE, de Koning EJ. Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice. Am J Physiol Endocrinol Metab. 2014 Mar 1;306(5):E552-8. doi: 10.1152/ajpendo.00453.2013. Epub 2014 Jan 7.
Kosinski C, Jornayvaz FR. Effects of ketogenic diets on cardiovascular risk factors: Evidence from animal and human studies. Nutrients. 2017 May 19;9(5). pii: E517. doi: 10.3390/nu9050517.
Kosinski C, Jornayvaz FR. [Ketogenic diets: the miraculous solution?] Rev Med Suisse. 2017 May 31;13(565):1145-1147.
Nei M, Ngo L, Sirven JI, Sperling MR. Ketogenic diet in adolescents and adults with epilepsy.
Seizure. 2014 Jun;23(6):439-42. doi: 10.1016/j.seizure.2014.02.015. Epub 2014 Mar 12.
Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr. 2013 Aug;67(8):789-96. doi: 10.1038/ejcn.2013.116. Epub 2013 Jun 26.
Pizzorno J. Acidosis: An old idea validated by new research. Integr Med (Encinitas). 2015 Feb; 14(1): 8–12.
Robey, IF. Examining the relationship between diet-induced acidosis and cancer. Nutr Metab (Lond). 2012; 9: 72. Published online 2012 Aug 1. doi: 10.1186/1743-7075-9-72
Schugar RC, Crawford PA. Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care. 2012 Jul;15(4):374-80. doi: 10.1097/MCO.0b013e3283547157.
According to the National Osteoporosis Foundation, up to one-half of women age 50+ will experience a bone fracture during the remainder of their lifetime. This means a lot of women will fracture, so it’s important to familiarize yourself with the better-documented fracture risk factors. Over the years, researchers have tried to quantify how much any factor increases the risk of bone fracture. Test your knowledge by taking this little quiz on 7 major risk factors — then check our chart below for the full list!
Chart: Top 7 bone fracture risk factors
Our quiz was just a fun way to enter this topic, but here’s a chart that you should take to heart. Look over the top 7 risk factors for bone fracture, ranked by risk ratio. This measure of “relative risk” represents the likelihood of a certain event happening in one group compared to the risk of the same event happening in another group.
|Risk factor||Risk ratio|
|Parental hip fracture||2.27|
|Low BMI (20 vs. 25)||1.95|
|Prior fragility fracture||1.85|
|High alcohol intake||1.68|
Are you concerned about risk factors that may be present in your life? Begin by assessing your personal health and lifestyle factors with our free Bone Health Profile. As we at the Center for Better Bones like to say, “It is never too late to begin building and rebuilding bone strength.”
Take action today!
Susan Ott, M.D. Website https://courses.washington.edu/bonephys/oprisk.html