Mimi Hu, M.D.
Assistant Professor
Department of Endocrine Neoplasia and Hormonal Disorders
The University of Texas MD Anderson Cancer Center
Hello, my name is Mimi Hu. I am an Assistant Professor with the Department of Endocrine Neoplasia and Hormonal Disorders at the University of Texas MD Anderson Cancer Center. This will begin the parts --- the second part of our Bone Health in Cancer Survivor lecture.
We're going to talk a little --- briefly on thyroid cancer and bone health.
In patients who have differentiated thyroid cancer, a modality of treatment is to suppress their TSH. And there aren't really great long-term studies that show the risk of bone loss or fracture in thyroid cancer patients. But we do see that in a large systematic meta-analysis that was published in JAMA in 2004, they looked at patients who had subclinical hyperthyroidism, which means TSH is suppressed but they don't have any symptoms of hyperthyroidism. And they did determine that there was a fair association that a --- patients who are postmenopausal women with a TSH less than 0.1 will have a decrease in bone density. But it was not seen in premenopausal women or men. Evaluating fracture risk, however, they felt that there was an insufficient association. But they did feel that women who were over 65 years of age and a TSH of less 0.1 had a potential higher risk of fracture and this was not seen in other pa --- other populations.
There was a systematic analysis of patients with well-differentiated thyroid cancer and looking at their bone health. And what they saw was that postmenopausal women with a TSH less than 0.5 had lower bone density than their control counterparts. But, again, this was not seen in premenopausal women or men. There was a study that showed that male patients with differentiated thyroid cancer did have higher levels of serum collagen telopeptide and osteocalcin levels, which are bone turnover markers, compared to healthy age mat --- age-matched controls. Whether this correlates with significant bone loss or fracture risk is unclear.
So, "What should be done in our cancer patients who might be at risk for bone loss?" First of all we need to identify our patients who are at an increased risk for bone loss. And then after evaluating their risk factors and screening for bone loss is to consider starting therapeutic intervention early enough to prevent further bone loss and prevent fractures, pain, and decrease in quality of life.
The American Soc --- the American Society of Clinical Oncology, in 2003, developed some guidelines for high risk breast cancer survivors in terms of surveillance for bone loss. They recommended that the following patients should be screened for bone loss: all women who are over the age of 65, postmenopausal women of any age receiving an aromatase inhibitor, women who are between the ages of 60 and 64 with a family history of bone loss or fracture, body weight less than 70 kilograms, previous non-traumatic fracture, or other risk factors that were described in the previous half of this discussion. Also patients who have premature menopause.
This is a graphic of an algorithm evaluate --- to help evaluate patients who have breast cancer for bone loss. If you find that the patient has risk factors and you get a bone density with a T-score of greater than or equal to minus 1, what's recommended is to provide lifestyle advice and begin calcium/vitamin D, and to reassure them. Patients who have bone density T-scores between minus 1 and minus 2.5, in the osteopenic range, we recom --- recommend again lifestyle and --- management and calcium/vitamin D, and to consider drug therapy on an individualized basis. Patients who have T-scores that are in the osteoporotic range, less than or equal to minus 2.5, besides offering lifestyle advice and beginning calcium/vitamin D, it's recommended to begin drug therapy. And here you see the various forms of medications that are currently approved for osteoporosis, including bisphosphonates such as alendronate, risedronate, ibandronate, and zoledronic acid, teriparatide, a synthetic parathyroid hormone, raloxifene, also a selected estrogen receptor modulator, and denosumab, a RANK ligand inhibitor.
In men, there's been less information in terms of guiding us in screening. Consensus guidelines for screening in men are not yet developed. Some authors have recommended that men on androgen deprivation therapy should be screened at baseline and yearly thereafter. When we look at men, we have to identify their risk for bone loss as --- if they are older then 70 years of age and this is consistent with what is recommended by the National Osteoporosis Foundation, if they have a low BMI or they have a prolonged duration of androgen deprivation therapy.
So this has been recommended before by Diamond et al. and published in Cancer, 2004. If a patient presents with any minimal --- low trauma fracture, or if they have a suspected vertebral fracture, or they have risk for fractures, or are --- are being treated with androgen deprivation therapy,- or previous --- or have had a previous fracture, we should move forward with screening, x-rays to confirm the fracture, and if they do have a confirmed fracture, then to begin bisphosphonate therapy. In the patients who have risk for bone loss, if you do a screening bone density and you see that their T-score is less than or equal to minus 2.5, in the osteoporotic range, it's recommended to begin bisphosphonate therapy. Patients who have osteopenic-range T-scores, it's recommended to repeat a bone density in another six to 12 months and then evaluate for loss over that duration of time. Those patients who have a normal bone density, it's recommended to do a bone density at two years. This is what was published in Cancer, 2004. However, we don't have long-term prospective studies to validate whether this is --- these guidelines are appropriate or not.
When we talk about lifestyle modifications, this is --- this slide doc --- lists the things that we can counsel our patients on. So we recommend that patients get adequate amounts of calcium and vitamin D from all sources and that includes what they get in their diet and also from supplements. In premenopausal women or men who are less than or equal to the age of 70, it's recommended that they receive a 1000 mg of calcium from all sources. And postmenopausal women or men over 70, 1200 mg of calcium from all sources. Vitamin D, it's recommended to receive between 800 and 1000 international units per day from all sources. Weight-bearing exercises and muscle strengthening exercises are quite important in helping to put some strain on the bones and actually stimulate osteoblastic activity and bone formation. Additionally, we recommend that patients avoid tobacco smoking and excessive alcohol intake, less than three drinks per day. And the rationale for this is based on the associations of other poor dietary habits in patients who tend to drink more than three drinks a day. If they're drinking more than three drinks a day, they're probably not drinking very much milk or other good healthy products. Also if they're smoking, they --- it seems to be associated with other poor lifestyle choices. But, additionally, we recommend that they limit their caffeine intake and also to limit their salt intake. And the rationale for lowering the salt intake is that patients who have high salty diets, they can lea --- have natriuresis, so salt loss in the urine, and when that happens, that can stimulate calciuresis and by pulling calcium into the urine, you are leading to potential demineralization of the bone.
So this is a calculation tool to try to estimate the calcium intake from calcium-rich foods. And you see an eight-ounce glass of milk has an estimated amount of 300 mg of calcium per serving, yogurt, 300 mg. And then fortified foods can have anywhere between 80 to 1000 mg. And then taking that total and adding on an additional 250 for non-dairy sources of calcium and that gives you a close estimate of what they're getting in their diet.
Vitamin D: We can find in things such as cod liver oil, cooked salmon, mackerel, tuna fish, those fatty fishes, sardines is an excellent source of vitamin D. Also fortified milk and cereals, and egg, liver, beef --- I'm sorry, beef liver, and also Swiss cheese, you see have the lowest amount of vitamin D in it.
And why do we recommend calcium/vitamin D? And we recommend it based upon this study that was published in 1997 by Dr. Dawson-Hughes in New England Journal. We see that patients who receive calcium and vitamin D as outlined here in the green bars had a lower risk of fracture compared to patients who did not receive any calcium/vitamin D on a daily basis. And this was seen in both men and in women.
Exercise: we can't stress exercise enough in our patients. Weight-bearing resistance training exercises are very important to help maintain bone --- bone mass. Unfortunately, a lot of times, our cancer patients are ill and sick or have other issues that might be limiting their exercise endurance. But anything that they can do to get them out of the bed and walking is helpful.
This outlines the various medications that we have available for treating osteoporosis. We do have salmon calcitonin as a nasal spray. There's a class of drugs called the bisphosphonates which includes alendronate, risedronate, ibandronate, and zoledronic acid, and also denosumab, recently approved, which is also --- is a RANK ligand inhibitor. Estrogen, in patients who can receive estrogen. We have selective estrogen receptor modulators, such as raloxifene, and also a synthetic parathyroid hormone called teriparatide. I bring our attention to the bisphosphonates because this is probably the most well-studied class of drugs for patients who have breast cancer and are postmenopausal.
In --- And here we see that antiresorptive therapy has been evaluated in premenopausal women, but in the setting of glucocorticoid therapy, primary hyperparathyroidism, or breast cancer patients who are receiving chemotherapy. So not as many studies in the premenopausal setting.
And bisphosphonates, the mode of action is that it will inhibit the farnesyl-pyrophosphatase, which is an enzyme in the HMG-CoA reductase pathway. By inhibiting this enzyme, you will prevent the post-translational prenylation that's necessary for this GTP-activated acidic ves --- these GTP-binding proteins which are very necessary to lead to these acidic vesicles to be formed. And these acidic vesicles are released through these ruffled borders to pres --- produce a[n] acidic environment that leads to bone resorption. So when you give a bisphosphonate, you inhibit these G proteins and you end up inhibiting the production of this ruffled border, and inhibiting this ability to produce this acidic environment. And it leads to osteoclastic apoptosis and decreasing its function.
In premenopausal women who are treated with breast cancer there was a large study called the ABCSG-12 study. These patients received endocrine therapy and they got either zoledronic acid or not.
And these patients were premenopausal so they received a gonadotropin re --- a GnRH agonist or gonadotropin-releasing hormone agonist called goserelin. And then, populations received either tamoxifen or anastrozole, and then they got either zoledronic acid or no zoledronic acid at 4 mg every six months. And this was a three-year treatment study. And what you see here is that the top two bars are patients who received, in the purple line and the green line, they received zoledronic acid. So if they were treated with anastrozole, in the green, or tamoxifen, in the purple, but also received zoledronic acid, you see that their bone density remained stable or slightly improved over the three-year treatment duration. And this improvement was even seen in the two years afterward, once therapy was discontinued. Compare that to the patients who did not receive zoledronic acid. When they received tamoxifen alone, there was a drop in bone density but not nearly as much as the patients who received anastrozole. So again, remember, tamoxifen may have a differential activity in patients who are --- who become menopausal. So goserelin led to the menopause in these patients and in that setting, tamoxifen actually was somewhat bone protective, comparing to the patients who received anastrozole. So this slide does show that zoledronic acid seems to be protective of --- for bone loss in these patients.
But, let's look at the details a little bit more in this study. What we see here is that these patients, prior to enrollment, they had normal bone density at baseline, and all patients with osteoporosis were excluded. So these are normal bone health patients who were placed on these adjuvant chemotherapy agents for their breast cancer and what you see, and I --- I do note that these --- this --- the font is small. But what you see here is that the patients who did not receive zoledronic acid, even at three years, their bone density, the mean difference from basely --- baseline went down 1.1 percent from their baseline. And that is comparing it to the patients who received zoledronic acid where there was no difference from baseline. So again, these patients are not having a significant drop in their T-scores of their bone density. And then despite medical therapy discontinuing after three years, when you follow these patients out to five years, the patients who did not receive zoledronic acid, their T-score actually went back up to a mean of about minus 0.6. And thus, this is not significantly different from their baseline.
This is another study that looked at bisphosphonates in women with breast cancer in the premenopausal setting. And this looked at patients who received placebo or risedronate in this setting, and 216 women received chemotherapy with anthracycline, taxane, or cyclophosphamide. They looked at their bone density at one year, and what you see here is that the patients who received risedronate had a 4.3 percent loss at one year, comparing it to the placebo group of 5.4 percent. So the conclusion was that risedronate did not prevent bone loss in the premenopausal women who were undergoing adjuvant chemotherapy for breast cancer. So in the premenopausal setting it's still a little bit unclear whether bisphosphonates significantly improves bone health and whether bisphosphonate in a premenopausal woman is necessary. And thus, at this time in our practice, we recommend taking each patient's case individually and analyzing their risk factors, maybe incorporating bone turnover markers, to clarify if a patient is at high risk for significant bone loss.
Now looking at the postmenopausal women, there --- this study showed that women who were treated with risedronate, here outlined in the black line, definitely had preservation of their bone density comparing those patients who received placebo. And this first slide is looking at the bone density. This other slide is looking at bone turnover markers where you see that the patients who received risedronate actually had a decrease in bone turnover markers compared to those patients who received placebo.
In the prostate cancer patients, look --- who are treated with androgen deprivation therapy, they looked at pamidronate, another bisphosphonate, at 60 mg every three months. And the patients who did not receive the bis --- bisphosphonate had a higher amount of bone loss compared to the patients who received pamidronate.
Zoledronic acid, another intravenous bisphosphonate, was also evaluated in prostate cancer patients who received androgen deprivation therapy. And you see here that the patients who received zoledronic acid had a[n] increase of bone density from baseline, comparing the patients who did not receive zoledronic acid. And this was seen at the --- the lumbar spine at 12 months.
Alendronate was also evaluated in patients who received androgen deprivation therapy and you see, again, that in the total hip that the bone density improves with alendronate comparing the patients who don't have --- who are on placebo up to one year. And this is in the spine and the total hip.
So bisphosphonates in cancer treatments: There are some limitations to the studies that have been published to date. First of all, we've had relatively small study populations; the duration of followup with treatment has been mostly between one to two years. Additionally, what you've seen here is primarily bone density preservation, but no information about change to fracture incidence. So --- and this is because you require much larger studies in order to evaluate fracture incidence. So most of these studies have been small and we've not been able to identify that. So it's --- it is unclear whether long-term treatment can offer benefit on our patients, especially when they start off with normal bone mass. Additionally, like I said before, there is no fracture prevention data in patients who've gotten bisphosphonate therapy. And as we use bisphosphonates longer we are identifying potential side effects such as osteonecrosis of the jaw and atypical femoral fractures. And thus, bisphosphonates use in our cancer posh --- population really needs to be determined with a weighing of risk factors and the potential benefits for each individual patient.
Denosumab is another type of drug that has been recently approved for osteoporosis. It is a fully human monoclonal antibody to the RANK ligand. And by binding to RANK ligand inhibits its interaction with the RANK receptor which is found on osteoclast precursors. And this will prevent osteoclast activation and formation, and inhibit bone resorption. It's given as a subcutaneous injection every six months and it has been evaluated in clinical trials with osteoporosis, cancer-related bone loss, and metastatic bone disease.
This study that was published in 2008, looked at denosumab in patients who received adjuvant aromatase inhibitor therapy. And you see here that the patients who receive denosumab had a higher --- had an increase in bone density over the course of 24 months comparing it to the patients who received placebo. And at 24 months, there was a 7.6 percent difference. This graph here shows that in this column, the place --- patients treated with placebo, and this column, patients treated with denosumab, and you see that 80 percent of the patients who were treated with denosumab actually had benefit and significant gain in their bone density compared to the patients who were treated with placebo.
In our prostate cancer patients, denosumab was also evaluated in --- when they received androgen deprivation therapy. And you see here that the patients who received denosumab had a lower new vertebral fracture percentage compared to the patients who received placebo therapy. And this was seen at 12 months, 24 months, and also 36 months.
So in summary, our new targeted therapies for cancer treatment has significantly improved survival. However, it --- it is associated with other side effects such as rapid bone loss in our patients. It's been seen that bone loss in our cancer posh --- population is associated with increased fracture risk. Lifestyle modification with dietary supplements or dietary changes and exercise, they are the cornerstone to strengthening bone health. And it's important for us as clinicians to remember to screen patients' bone density in the appropriate population
Early antiresorptive therapy could prevent significant deterioration of bone density in patients who have osteoporosis or low bone mass. Whether this is validated in our patients with normal bone density and improving their overall bone health long-term is still questionable. Standard protocols and long-term follow-up of our cancer survivors are truly needed to clarify clinically relevant benefits to their bone health and their quality of life. This concludes the Part 2 of this topic on Bone Health in Cancer pa --- Population. We welcome your feedback and I thank you for your attention.
Bone Health in Cancer Survivors, Part 2 video
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