From the North American Menopause Society website, discussants Dr. Marla Shapiro, Past President of NAMS, and Dr. Cynthia Stuenkel, Past President of NAMS and professor at the University of California at San Diego
Once you have been diagnosed with osteoporosis, have had an osteoporotic fracture, or it has been determined that your FRAX score is high, treatment with medication is indicated. So many women have misconceptions about the medications, their risks and benefits. Let’s go through the categories of medication and options in each category.
This is a category of drugs that decreases re-absorption of old bone. We all have osteoclasts that are cells in our bones that remove old bone, and osteoblasts that put down new bone. Prior to menopause, the osteoblasts are more active than the osteoclasts, and new bone is formed at a higher rate than bone is lost. This changes at menopause, and with other conditions of low estrogen such as anorexia, prolonged lactation, and use of aromatase inhibitors. . Bisphosphonates work by decreasing the function of the osteoclasts.
There are 4 bisphosphonates: alendronate, risedronate, ibandronate, and zoledronate.
These drugs can be given orally or IV. All bisphosphonates decrease vertebral fractures from 35-65%. Both alendronate and zoledronate significantly reduce hip fractures also, and risedronate reduces non-vertebral fractures. If taken orally, the drug must be taken on an empty stomach with 8 ounces of water, and patients are advised to sit or stand for 30-60 minutes after ingestion to avoid reflux that could cause esophageal irritation. If the medication is taken with food or other drugs, the absorption of the drug is diminished and it will be less effective. These drugs remain active in the bone for some time after discontinuation of the drug. Alendronate specifically will remain in the bone for 5 years after the last dose, and the bone density will usually decline slowly during this time. This allows for patients to take drug holidays, without losing most of the benefits gained. Risedronate users had significant loss of bone in the first year after discontinuation.
Zolendronate is a once-yearly infusion. It cannot be given to patients with acute renal failure or a creatinine clearance of less than or equal to 35 mL/min.
Press reports have over-emphasized the side effects of this class of drugs. Side effects can include musculoskeletal aches and pains, gastrointestinal irritation and ulcers of the esophagus. More severe side effects including osteonecrosis of the jaw and atypical fractures of the femur are very rare, occurring in about 1/10,000 years of use. Since most women who take these drugs have a 20% risk of any fracture, and a greater than 3% risk of a hip fracture in the next 10 years, the risk/benefit ratio is far in favor of a benefit. Because of the long-term duration of effect of the bisphosphonates, it does not make sense to stop the drug during a dental procedure. It does make sense to have frequent dental exams while taking the medication, as osteonecrosis of the jaw, if caught early, is treatable. It also makes some sense to have any invasive dental work completed before starting bisphosphonate use.
Dosing of the bisphosphonates vary from orally weekly to monthly, and IV from every 3 months to yearly, depending on the drug. Patients with upper GI problems might consider intravenous administration, or a short-term trial of an oral agent.
Selective estrogen agonists/antagonists:
Raloxifene is a selective estrogen receptor modulator, or a SERM. This type of drug was designed by scientists to act like estrogen in certain parts of the body, while acting as an anti-estrogen in other parts of the body. Raloxifene acts like estrogen in the bone. Because of this, it is an anti-resorptive drug, preventing the resorption of old bone. It has been shown to reduce vertebral fractures. In the breast, raloxifene acts as an anti-estrogen, so a beneficial side effect is that it reduces the risk of postmenopausal breast cancer in women who have osteoporosis, even if they are at high risk of developing breast cancer.
This drug is taken orally, once a day and is usually well-tolerated. It can increase hot flashes, especially in women who are newly menopausal and who are still having vasomotor symptoms.
More serious side effects include blood clots in the legs and deaths from stroke, although the incidence of stroke is not increased. This drug is especially beneficial for women with osteoporosis who are at increased risk of breast cancer. Five years of use will reduce the subsequent risk of breast cancer by at least 50%.
Denosumab is a mono-clonal antibody that works in the cascade of molecules that affect the function of the osteoclast. The drug inhibits a pathway that leads to de-activation of the osteoclast, and thus less bone is reabsorbed. This drug has been available since 2010, and has been shown to reduce vertebral fractures by 68% and hip fractures by 40%. It is given subcutaneously by injection twice a year. Prior to administration, it is important to check the calcium level of the patient.
This drug is very well tolerated. It is believed that the risk of osteonecrosis of the jaw and atypical femoral fractures is very low. There is a significant increase in infections that were noted in clinical trials, but in practice, this risk is very low. Occasionally a patient will note musculoskeletal pain after injection, but again, this is infrequent.
Because the bone density can decrease significantly after this drug is stopped, and the fracture risk does increase in the first year, discontinuation of drug should be followed by a maintenance medication.
Calcitonin is administered as a nasal spray has been used for the reduction of vertebral fractures, but it is not as effective as other agents. It can be effective in women who have painful vertebral fractures by diminishing the pain.
Teriparatide or recombinant human parathyroid hormone stimulates the osteoblasts to produce more bone, therefore it is considered an anabolic (growth) hormone, rather than an anti-resorptive agent. It improves the micro-architecture of the bone, making it stronger. The drug is given daily and subcutaneously, therefore it is self-administered by the patient, and can only be given for two years. In animal studies, use more than two years increased the incidence of bone cancers, but this has not been seen in humans. After discontinuation of the drug, a patient must be switched to another medication to maintain the benefit.
This medication has been found to decrease the risk of vertebral and non-vertebral fractures. Side effects include nausea, dizziness, and muscle cramps, but since it is a daily dose, it can be discontinued easily.
Parathyroid hormone is often used in cases where the bone density decreases despite use of other drugs, or after a fracture has been sustained. Because it can only be used for two years, it must be part of a long-term strategy.
Estrogen is a potent anti-resorptive agent, and it is well known that bone density decreases significantly in the first five years of menopause. In the Women’s Health Initiative, vertebral and hip fractures were reduced about 35% by hormone therapy. Hormone therapy is approved for the prevention of osteoporosis in women at risk. Even very low dose estrogen patches have a benefit in the reduction of osteoporosis, although the benefit is dose-related. Hormone replacement therapy should be an important part of the conversation as a women enters menopause and considers her symptoms and goals, her family history and risk factors, and the type of treatment most suited to her individual situation. Most women can take combined estrogen and progesterone for at least five years with no increase in breast cancer, and longer if she is using estrogen only. After discontinuation of HRT, loss of bone density can be rapid and the benefit can be lost in two years, so monitoring bone density and adding another drug should be considered.
In the next chapter, we will look at drug holidays and try to put concerns about serious side effects in perspective.
Foxhall OB-Gyn Associates
The. American College of Obstetricians and Gynecologists. Practice Bulletin. Osteoporosis,
Number 129, September 2012
When you receive your mammogram report, you may note that at the end of the report it states that your breasts are dense and that this may limit the accuracy of the mammogram. This can be frightening to a patient: going through the procedure just to be told that it may miss a breast cancer because of dense tissue. What does that really mean?
The breasts are composed of glands and fat. The glands are composed of the lobules that produce milk and the ducts that bring the milk to the nipple. Fat surrounds the breast tissue. Most breast cancers arise from the ducts. Lobular cancers are less common.
We know that very dense breast tissue can increase the risk of breast cancer 4-6 times.
The reason for this is that the tissue that is dense is more actively growing and dividing which allows mutations that can lead to cancer. Also, the glandular tissue may be more hormonally sensitive.
According to the American College of Radiology, breast density is divided into four categories:
If your breasts are extremely dense or heterogeneously dense, they would be considered dense breasts. About 40% of women over the age of 40 will fit into this category.
Most women will fit into category 2 or 3.
So what does a mammogram look for?
A mammogram is looking for a mass which would often appear as an irregular white density, with irregular borders, sometimes containing calcifications. Non-invasive breast cancer or DCIS is microscopic disease, and often there is no mass present. Calcification that are clustered, fine, and irregular are often seen in breast cancer masses.
If your breasts are considered dense, what type of screening should you have? Is yearly mammography enough?
The answer to this depends on your age and other risk factors. Your physician should take into account your family history, BRCA gene status, a history of breast irradiation prior to the age of 30, and a history of previous breast biopsies. There are several models that can predict the risk of breast cancer taking into account multiple factors, but these models don’t take into account breast density as a risk factor.
The Gail Model risks takes into account your age, age at first menstrual cycle, age at first live birth, number of first degree relatives with breast cancer, how many breast biopsies you have had, and if any demonstrated abnormal cells.
The Tyrer-Cusick Model looks at age, weight, height, age of first menses and menopause, whether you have taken HRT and how long, your BRCA status if known, and and extensive family history of breast and ovarian cancer.
If either determines that your lifetime risk is greater than 20%, you would be considered at higher risk, and supplemental screening is optional. Remember that average lifetime risk of breast cancer is about 12%.
We know that mammography saves lives, because it can find invasive breast cancers before it spreads to lymph nodes. Whether additional screening with ultrasound of MRI actually saves lives has never been proven with studies. Most of the breast cancers found on sonogram or MRI that are not detected by mammogram are small and are lymph node negative. It is possible that some of these cancers are very slow growing and would have never been life-threatening.
Options for additional screening include 3D tomosynthesis, ultrasonography, or a breast MRI. Additional screening is recommended for women who carry the BRCA gene, or women who have had radiation to the chest (usually for Hodgkin’s disease before age 30). Insurance coverage for additional screening depends on the insurance carrier, and sometimes the state in which the study is done. An MRI can cost several thousand dollars, so insurance coverage criteria should be confirmed prior to administering the test.
Despite breast density, mammography, especially 3D mammography should always be the first screening tool used. A 2D mammogram will pick up 2-7 breast cancers per 1000 women screened. A 3D mammogram will pick up 3-9 breast cancers per 1000 women screened.
Adding sonography to a 2D mammogram will pick up 4-11 breast cancers per 1000. A 2D mammogram plus a contrast-enhanced MRI will pick up 12-17 breast cancers per 1000.
The decision to perform additional screening for breast cancer beyond a 2D or 3D mammogram is, in many cases, is a complex process, taking into account many factors, and breast density should be considered in that equation. By being better informed, and with the advice of your physician, an appropriate decision can be made for each individual woman.
Marilyn Jerome, MD
Foxhall Ob-Gyn Associates
OBG Management, Volume 27, Number 10, October 2015. Get smart about dense breasts.
Berg, et al.