ASCO Backs Bone Drugs for Myeloma


Recommended for patients with or without evidence of lytic damage

Patients with symptomatic multiple myeloma should receive bone-modifying therapy irrespective of evidence of lytic destruction or spinal compression fracture, according to an updated guideline from the American Society of Clinical Oncology (ASCO).

Treatment options consist of the intravenous bisphosphonates pamidronate and zoledronic acid (Zometa) or, alternatively, the RANK ligand inhibitor denosumab (Xgeva). Denosumab might be preferred over zoledronic acid for patients with renal impairment, as the RANKL inhibitor has been associated with fewer renal adverse events.

 The primary purpose of the update, and associated expert-panel review, was to determine whether the 2007 recommendations remain valid. ASCO initially published clinical guidance about the use of bone-modifying agents in myeloma in 2002.

“These recommendations are consistent with the previous recommendations, with new information on denosumab,” the guideline authors stated. “Additional modifications were made to some of the recommendations on the basis of recent data to better clarify the indications for treatment, duration of treatment, and associated complications of treatment.”

The panel, chaired by Kenneth Anderson, MD, of Dana-Farber Cancer Institute in Boston, and Robert A. Kyle, MD, of the Mayo Clinic in Rochester, Minnesota, updated the ASCO recommendations after examining 35 relevant studies identified by means of a targeted systematic literature review. The review included randomized controlled trials, systematic reviews, meta-analyses, clinical practice guidelines, and observational studies.

Key recommendations included:

  • Initiate bone-modifying therapy for patients with imaging-based evidence of lytic disease and for patients with osteopenia in the absence of lytic disease
  • Use bone-targeted agents as adjunctive therapy for controlling pain associated with osteolytic disease and for patients receiving other interventions for existing or impending fractures
  • Initiate intravenous bisphosphonates in patients with normal radiographs or osteopenia by bone mineral density measurements
  • Do not use bone-modifying agents in patients who have monoclonal gammopathy of undetermined significance, except when osteopenia exists
  • Reduce the dose of zoledronic acid in patients who have pre-existing mild or moderate renal impairment
  • Consider denosumab as an alternative to zoledronic acid for patients with compromised renal function
  • Use serum creatinine monitoring before each dose of a bisphosphonate, in accordance with FDA labeling
  • Perform intermittent evaluation of all bisphosphonate-treated patients for presence of albuminuria

The updated guideline also includes a table with the estimated cost of bone-modifying agents. Pamidronate and zoledronic acid had per-dose costs of $30.67 and $53.64, respectively, whereas each dose of denosumab cost $1,995.48. The estimated 1-year costs were $398.71 for pamidronate, $214.56 for zoledronic acid administered every 12 weeks, $697.37 for zoledronic acid every 4 weeks, and $25,9341.24 for denosumab every 4 weeks.

A compendium of ASCO recommendations related to bone-modifying therapy in myeloma is available on the organization’s website. The update was also published in the Journal of Clinical Oncology.

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Bisphosphonates Curb Bones Breaks in Women With T2D


Bisphosphonate therapy was effective for reducing fracture incidence among postmenopausal women with diabetes, a post hoc analysis of randomized trial data found.

Among women with diabetes, the relative risk of nonvertebral fracture was 0.52 (95% CI 0.33-0.80) and the relative risk of morphometric vertebral fracture was 0.34 (95% CI 0.18-0.67), reported Ann Schwartz, PhD, of the University of California San Francisco, at theAmerican Society for Bone and Mineral Research meeting.

For nondiabetic women, the relative risks of nonvertebral and vertebral fractures were 0.83 and 0.39, respectively.

“Clearly, the bisphosphonate treatment was protective in both diabetic and nondiabetic women,” she said.

Type 2 diabetes is associated with a higher fracture risk at a given bone density, but the reasons for this greater bone fragility are unclear. However, there is evidence that diabetic bone is characterized by reduced bone formation and higher levels of advanced glycation end products.

“One hypothesis is that this accumulation of advanced glycation end products contributes to the bone fragility in diabetic bone. This has led to a theoretical concern that bisphosphonates, which have an antiresorptive mechanism of action, might not be an effective treatment for fracture prevention in this setting,” she said.

To test this hypothesis, she and her colleagues analyzed data from two randomized trials, the Fracture Intervention Trial (FIT) of alendronate (Fosamax) and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) pivotal fracture trial.

FIT included just under 6,500 postmenopausal women whose femoral neck T-score was -1.6 or lower and who received alendronate, 5 to 10 mg/day or placebo for up to 4 years. Their mean age was 68 and mean body mass index (BMI) was 25.1 kg/m2.

HORIZON enrolled more than 7,700 women with osteoporosis based on their femoral neck T-score and who were given a once-yearly infusion of 5 mg zoledronic acid for up to 3 years. Their mean age was 73 and mean BMI was 25.3 kg/m2.

Diabetes was ascertained by self-report or by self-report of use of an antidiabetic medication. Fasting glucose levels were available for the women in HORIZON and for 20% of the women in FIT, and for others nonfasting glucose levels were used.

In FIT, 4.2% of participants had baseline diabetes, as did 7.7% in HORIZON. Most of the women were probably type 2 diabetics, although this was not specifically ascertained, Schwartz noted.

For the analyses of fractures, the two studies were combined.

Overall, 87 of 869 women with diabetes experienced one or more nonvertebral fracture, as did 1,411 of 13,288 women without diabetes.

Morphometric vertebral fractures were reported in 44 of 769 diabetic women and in 786 of 12,312 nondiabetic women.

In both FIT and HORIZON, bone turnover markers also were suppressed in both diabetic and nondiabetic women, supporting the finding that the anti-fracture efficacy of bisphosphonate therapy was not inferior in diabetic women, Schwartz concluded.

A limitation of the study was its post hoc design, in which assessment for diabetes was not part of the original protocol.

Bisphosphonates Linked to Lower Endometrial Cancer Risk


A class of drugs that prevents bone loss may also help reduce women’s risk of developing endometrial cancer, according to a new study published online December 22 in Cancer.

Women who had a history of taking bisphosphonates were about half as likely as women who had not taken the drugs to develop endometrial cancer.

The study looked only at bisphosphonates that contain nitrogen, which have the strongest anticancer effects among the class of drugs, according to prior studies.

Sharon Hensley Alford, PhD, from the Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan, and colleagues looked at data from 29,254 women aged 60 years and older in the National Cancer Institute’s Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. The survey included a questionnaire on bone health and use of medications, including bisphosphonates.

Among the women who had used bisphosphonates, the researchers saw 8.7 cases of endometrial cancer per 10,000 person-years, compared with 17.7 cases per 10,000 person-years among women who had never used the drugs (rate ratio, 0.49; 95% confidence interval, 0.30 – 0.80).

After adjusting for a variety of variables, including age, race, smoking history, hormone therapy history, and body mass index, the hazard ratio for women taking the drugs compared with those not taking them was 0.56 (95% confidence interval, 0.34 – 0.93).
Endometrial cancer is the fourth most common cancer in women and the eighth most common cause of cancer death. Nearly half of all gynecologic cancers are endometrial. Endometrial cancer is most often diagnosed in women in their 60s and 70s, when they are postmenopausal and their bone density has decreased.

Previous research showed that bisphosphonates can slow tumor growth and the spread of cancer cells in patients with certain types of cancer, but no study had specifically looked at endometrial cancer.

The study’s main findings focused on the more common type 1 endometrial cancer, which is related to high estrogen levels. Researchers called for further studies with a larger sample to better assess the drug’s relationship to the more aggressive type 2 endometrial cancer, which is not hormonally related.

 

Bisphosphonates may hold potential for treatment, prevention of some cancers


Bisphosphonates could potentially be repurposed for the prevention and adjunctive therapy of cancer driven by human epidermal growth factor receptors, according to research published in the Proceedings of the National Academy of Sciences.

Through connectivity mapping, researchers at the Icahn School of Medicine and the Tisch Cancer Institute, both at Mount Sinai, identified human epidermal growth factor receptors (HER) as a potential molecular entity for bisphosphonate action.

“Our study reveals a newfound mechanism that may enable the use ofbisphosphonates in the future treatment and prevention of the many lung, breast and colon cancers driven by the HER family of receptors,” Mone Zaidi, MD, director of the Mount Sinai Bone Program and a member of the Tisch Cancer Institute, said in a press release.

Mone Zaidi

Mone Zaidi

“Having already been approved by the FDA as effective at preventing bone loss, and having a long track record of safety, these drugs could be quickly applied to cancer if we can confirm in clinical trials that this drug class also reduces cancer growth in people,” Zaidi said. “It would be much more efficient than starting drug design from scratch.”

Zaidi, with Tony Yuen, PhD, also of the Tisch Cancer Institute, and colleagues from institutions around the globe used protein thermal shift and cell-free kinase assays, with computational modeling.

Bisphosphonates bind to the kinase domains of HER proteins, preventing abnormal growth signals from passing on; this includes the forms of the protein family making some tumors resistant to leading treatments, according to the release.

Results encompassed four types of tyrosine kinase receptors — HER1, HER2, HER3 and HER4 — that occur on the surfaces of cells, regulating division and proliferation.

Once a bisphosphonate-receptor connectivity map link was digitally detected, the scientists conducted experiments in cancer cell cultures that validated the potential of treating HER-driven cancers with the drugs alone and in conjunction with the approved tyrosine kinase inhibitor erlotinib (Tarceva, OSI Pharmaceuticals), according to the release.

The research was published with a second paper, by several of the same researchers at Mount Sinai and abroad, that examines repurposing of bisphosphonates for the prevention and therapy of non–small cell lung and breast cancer.

“While this finding is exciting, there is no business model for conducting the costly clinical trials that would be needed to repurpose bisphosphonates for cancer,” Zaidi said in the release. “Pharmaceutical companies are unlikely to pay for research to develop generic drugs where there is no chance of patent protection or profit, so we will be looking for a nontraditional funding source, perhaps the federal government.”

Osteoporosis Drugs Lower Fracture Risk, but Best One Unclear


Several medications are able to reduce fracture risk in individuals with bone density in the osteoporotic range and/or preexisting hip or vertebral fracture, according to a systematic review published online September 9 in the Annals of Internal Medicine. However, a paucity of comparative studies makes it difficult to determine the relative effectiveness of the medications.

Effective drugs include bisphosphonates, denosumab, teriparatide, and raloxifene, report Carolyn J. Crandall, MD, from the David Geffen School of Medicine at the University of California, Los Angeles, and colleagues.

Given the lack of head-to head trials, differences in adverse effect profiles may be key for physicians and patients when choosing which drug to use, the authors note.

The authors screened 52,000 titles and found very few head-to-head comparisons between different medications used to treat osteoporosis. The ongoing Vertebral Fracture Treatment Comparisons in Osteoporotic Women (VERO) study will be completed in 2016, however, and the resulting data should shed some light on the relative efficacy and safety of the different options.

On the basis of that trial and on the observational study data that are available, Dr. Crandall and colleagues estimate that bisphosphonates, denosumab, and teriparatide treatment result in a risk reduction for vertebral fractures of 0.40 to 0.60 relative to placebo. The relative risk reduction for nonvertebral fractures was 0.60 to 0.80. Raloxifene has only been demonstrated to reduce vertebral fractures.

In other words, they estimate 60 to 89 patients need to be treated with a bisphosphonate, denosumab, teriparatide, or raloxifene to prevent 1 vertebral fracture over the course of 1 to 3 years of treatment. Fifty to 60 patients need to be treated with a bisphosphonate, denosumab, or teriparatide to prevent a single nonvertebral fracture.

Adverse Event Profiles Differ

Dr. Crandall and colleagues note that atypical subtrochanteric femur fracture is a newly recognized adverse event of bisphosphonate use. The adverse event has not been detected in clinical trials, which are not powered to detect rare events, but 2 studies that used either meta-analyses or large safety databases put the hazard ratio for the serious adverse event at 1.70 and 4.51, respectively.

The more common adverse events, such as gastrointestinal effects, hot flashes, chills, and cardiovascular events, differ between agents, but no agent is without adverse effects.

Few Data for Older Patients

In an accompanying editorial, Heike A. Bischoff-Ferrari, MD, DrPH, from the University of Zurich and Otto Meyer, MD, from the City Hospital Waid in Zurich, Switzerland, point out that a major limitation in the systematic review is that it does not reflect data for women who are older than 80 years.

Approximately 75% of osteoporotic fractures occur in patients who are 65 years of age or older, and many of these patients are older than 80 years.

There is a major limitation in the systematic review, however: It does not reflect data for women who are older than 80 years. Approximately 75% of osteoporotic fractures occur in patients who are 65 years old or older, and many of these patients are older than 80 years.

The aging of the Western population has resulted in patients older than 80 years increasingly being included in clinical trials of pharmacologic treatments for the prevention of fractures. For example, the Hip Intervention Program trial of risedronate included women aged 70 to 79 years as well as a second group of women aged 80 years or older. Although risedronate was effective in the first group, it did not reduce hip fracture risk in women aged 80 years or older.

The Hip Intervention Program trial represents just 1 study of this vulnerable population. The results from other studies of older patients are not yet in. “Because these patients sustain most fragility fractures, their insufficient representation in current clinical trials of pharmacologic treatments against fractures warrants emphasis,” write Dr. Bischoff-Ferrari and Dr. Meyer.

This absence of data led Dr. Bischoff-Ferrari and Dr. Meyer to write that, “Although this is helpful information to guide clinicians and their patients, we believe that they should recognize that these conclusions may not apply to patients aged 75 years or older, and especially not to those aged 80 years or older with nonskeletal risk factors for falls. Such patients are insufficiently represented in the clinical trials of pharmacologic treatments for fracture prevention included in this careful evidence review.”

 

FDA Approves Binosto.


The U.S. Food and Drug Administration (FDA) has approved Binosto (alendronate sodium) Effervescent Tablets for the treatment of osteoporosis in postmenopausal women, and as a treatment to increase bone mass in men with osteoporosis.

What is Binosto?

Binosto contains alendronate, which is in the group of medicines called bisphosphonates. It alters the cycle of bone formation and breakdown in the body. Alendronate slows bone loss while increasing bone mass, which may prevent bone fractures.

 

Binosto is used to treat osteoporosis in postmenopausal women, and as a treatment to increase bone mass in men with osteoporosis.

Binosto may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Binosto?

Do not take a tablet containing alendronate (such as Binosto) if you cannot sit upright or stand for at least 30 minutes. Alendronate can cause serious problems in the stomach or esophagus (the tube that connects your mouth and stomach). You will need to stay upright for at least 30 minutes after taking this medication.

Take the Binosto tablet once weekly first thing in the morning, at least 30 minutes before you eat or drink anything or take any other medicine.

Dissolve the Binosto tablet in half a glass (4oz) of plain room temperature water. Binosto is a strawberry flavored effervescent tablet which dissolves rapidly.

For at least the first 30 minutes after taking a tablet containing alendronate (such as Binosto), do not lie down or recline; do not eat or drink anything other than plain water; and do not take any other medicines including vitamins, calcium, or antacids.

Some people using medicines similar to alendronate have developed bone loss in the jaw, also called osteonecrosis of the jaw. Symptoms may include jaw pain, swelling, numbness, loose teeth, gum infection, or slow healing after injury or surgery involving the gums. You may be more likely to develop osteonecrosis of the jaw if you have cancer or have been treated with chemotherapy, radiation, or steroids. Other conditions associated with osteonecrosis of the jaw include blood clotting disorders, anemia (low red blood cells), and a pre-existing dental problem.

If you need to have any dental work (especially surgery), tell the dentist ahead of time that you are using alendronate. You may need to stop using the medicine for a short time.

Talk with your doctor about the risks and benefits of using this medication.

What should I discuss with my healthcare provider before taking Binosto?

Do not take any tablet containing alendronate (such as Binosto) if you cannot sit upright or stand for at least 30 minutes. Alendronate can cause serious problems in the stomach or esophagus (the tube that connects your mouth and stomach). You will need to stay upright for at least 30 minutes after taking this medication. You should not take alendronate if you are allergic to it, or if you have low levels of calcium in your blood (hypocalcemia), or a problem with the movement of muscles in your esophagus.

To make sure you can safely take alendronate, tell your doctor if you have any of these other conditions:

  • trouble swallowing;
  • a vitamin D deficiency;
  • a dental problem;
  • kidney disease; or
  • an ulcer or other problem in your stomach or esophagus.

Some people using medicines similar to alendronate have developed bone loss in the jaw, also called osteonecrosis of the jaw. Symptoms may include jaw pain, swelling, numbness, loose teeth, gum infection, or slow healing after injury or surgery involving the gums.

You may be more likely to develop osteonecrosis of the jaw if you have cancer or have been treated with chemotherapy, radiation, or steroids. Other conditions associated with osteonecrosis of the jaw include blood clotting disorders, anemia (low red blood cells), and dental surgery or pre-existing dental problems.

Talk with your doctor about the risks and benefits of using this medication.

FDA pregnancy category C. It is not known whether alendronate will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether alendronate passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

See also: Binosto pregnancy and breastfeeding warnings (in more detail)

How should I take Binosto?

Take Binosto exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Binosto tablets are taken once each week.

Take the Binosto tablet first thing in the morning, at least 30 minutes before you eat or drink anything or take any other medicine. Take the Binosto tablet on the same day each week and always first thing in the morning.

Dissolve the Binosto tablet in half a glass (4oz) of plain room temperature water. Swallow the entire amount to ensure you have taken the entire dose.

After taking a Binosto tablet, carefully follow these instructions:

  • Do not lie down or recline for at least 30 minutes after taking.
  • Do not eat or drink anything other than plain water.
  • Do not take any other medicines including vitamins, calcium, or antacids for at least 30 minutes after taking Binosto. It may be best to take your other medicines at a different time of the day. Talk with your doctor about the best dosing schedule for your other medicines.

To be sure this medication is helping your condition, your bone mineral density will need to be tested on a regular basis. Visit your doctor regularly.

If you need to have any dental work (especially surgery), tell the dentist ahead of time that you are using Binosto. You may need to stop using the medicine for a short time.

Binosto is only part of a complete program of treatment that may also include diet changes, exercise, and taking calcium and vitamin supplements. Follow your diet, medication, and exercise routines very closely.

Store at room temperature away from moisture and heat.

What happens if I miss a dose?

If you forget to take Binosto on your scheduled day, take it first thing in the morning on the day after you remember the missed dose. Then return to your regular weekly schedule on your chosen dose day. Do not take two (2) tablets in one day.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Drink a full glass of milk and call your local poison control center or emergency room right away. Do not make yourself vomit and do not lie down.

Overdose symptoms may include nausea, heartburn, stomach pain, diarrhea, muscle cramps, numbness or tingling, tight muscles in your face, seizure (convulsions), irritability, and unusual thoughts or behavior.

What should I avoid while taking Binosto?

Avoid taking any other medicines including vitamins, calcium, or antacids for at least 30 minutes after taking an alendronate tablet such as Binosto. Some medicines can make it harder for your body to absorb alendronate. Do not lie down for at least 30 minutes after you take a Binosto tablet.

Source: FDA news.