Introduction
When lifestyle measures are not enough, medicines play an important role in the treatment of postmenopausal women and men with osteoporosis. Those individuals at high risk for fracture will benefit most from prescription medicine treatment. In general, you are considered to be at high risk if you have already had a fracture (including silent spine fractures), have low bone density with multiple risk factors, have bone density in the osteoporosis range (T-score below -2.5), or are losing bone rapidly. Assess your risk with your doctor to make sure prescription medicines are indicated. In addition, decrease any modifiable risks and assure adequate daily calcium and vitamin D with supplements as needed.
Matching your needs with the right available medicine is essential. The medicine you start with may not be the one you continue to use year after year. Always re-evaluate its use and need on an annual basis with your doctor. New research will continue to provide new information and offer new choices. Some of you may not be interested in prescription medicines at all. If you have low bone density, most likely your doctor will discuss medicines with you. Whether you are considering prescription medicines or alternative therapies, I encourage you to look at all the available evidence to ensure that the option you choose will actually decrease your risk of fractures.
HOW DO BONE MEDICINES WORK?
The medicines for osteoporosis either slow the breakdown of bone by interfering with the demolition cells (osteoclasts) or boost the formation of bone by turning on the bone-builder cells (osteoblasts). The medicines are divided into two categories depending on their target of action. The term “antiresorptives” refers to the medicines that target the cells responsible for bone breakdown. Most antiresorptives are in the bisphosphonate class of medicines. “Anabolics” is the name for those medicines that turn on the bone-builder cells that form new bone. Forteo® is the sole member of the anabolic group.
A repeat bone density test after two years of treatment is indicated. Therefore, the typical improvement in bone density from clinical trial data at two years is given for each of the FDA-approved medicines in the next sections. If you and your doctor are worried about rapid bone loss, then you will need a repeat bone density sooner. Your repeat DXA should be done at the same facility that performed your baseline test in order to get an accurate comparison. Schedule a follow-up appointment with your doctor to go over the results. Your repeat bone density should show no change from the baseline results (stable) or increases at both your hip and spine. Stable is good and represents a treatment response. Keep in mind that small changes in bone density account for large decreases in fracture risk. If the numbers indicate a loss of bone density while on treatment, refer to the section on monitoring (page 311).
For medicines to work, you need to take them. If you expect to get the benefits shown in clinical trials for reducing risk of fracture, you need to follow the dosing regimen for the medicine as directed by your doctor. Too often, medicines are not taken as prescribed or the medicines are stopped altogether without consulting with the prescribing doctor. Keep an open dialogue with your doctor if you are having difficulty with the medicine or have doubt about taking it.
What Is a Randomized Clinical Trial?
All FDA-approved medicines for treating osteoporosis have been proven to reduce the risk of spine fractures and sometimes other types of fractures in what is called a randomized, placebo-controlled clinical trial. These studies are referred to as the “pivotal fracture trials.” This means that the FDA has participated in discussions with a sponsor regarding the design and conduct of the trial. In addition, the FDA assigns its own statisticians to review the data and it audits some of the study sites.
The diagram displays a typical design and the numbers of participants that are required in order to show differences in rate of fractures over three years. To qualify for entry into the study, prospective participants are carefully screened with questionnaires about their history, DXA scans, spine x-rays, and laboratory tests to see if they meet the entry criteria. If they meet the qualifying bone density or have a spine fracture and no conflicting factors that could influence response to therapy, they are eligible. Those who do not meet the entry criteria are excluded from participating in the study.
The eligible subjects are divided randomly into groups to receive the active study medicine or a look-alike dummy medicine called a placebo. In the osteoporosis studies, both the active and placebo groups received supplements of calcium and vitamin D. The participants, staff, researchers, monitors, and statisticians are all “blinded,” meaning that no one knows the medicine assignment until the study is completed. The randomization process equalizes multiple features such as age, weight, and bone density so the groups are the same. Therefore, the differences measured at the end of the study will be due to the study medicine. During the study, the subject reports any illness or problem that occurs at each clinic visit. All subjects are monitored closely for safety, bone density changes, and fractures.
For the pivotal fracture trials, fracture risk reduction is determined by comparing fracture rates in the treated group with those in the placebo group. When statistical analysis of the data shows a significant reduction in spine fractures and the benefit-risk profile is felt to be favorable, the drug is likely to be approved for use in clinical practice by the FDA.
If you make a decision to start one of these medicines, you need to be sure that your risk of fracture is high enough to justify starting therapy. Fracture risk assessment with tools like FRAX helps quantify your risk and serves as a starting point for discussion of your individual risk. No medicine is risk free. Keep in mind that these FDA-approved medicines have all been through rigorous testing with thousands of people studied in a controlled setting. After approval, sometimes unforeseen problems appear that were not observed during the clinical trials. The FDA continues to monitor for these situations. In 2007, the FDA implemented an even stronger safety program. For some newer medicines, there are voluntary programs open to your participation to capture any problems that might arise.
Remember, treatment with medicine is not a panacea; it must be in combination with general measures of adequate calcium and vitamin D, nutrition, exercise, and fall prevention. You have to do your part in making healthy choices, exercising, and taking your medicine as prescribed.
OSTEOPOROSIS MEDICINES
APPROVED FOR A RANGE OF
OSTEOPOROSIS INDICATIONS
The medicines approved for osteoporosis by the FDA have specific indications for use. Treatment of postmenopausal osteoporosis is based on the effectiveness shown in decreasing risk of fractures in the pivotal fracture trial for each medicine. The fracture trials use the largest number of subjects in order to show fracture effectiveness. Additional indications are based on smaller studies that look at bone mineral density. The assumption is that equivalent bone density changes will confer the same fracture reduction benefit.
Fosamax (and Generic Alendronate):
The First Kid on the Block
The approval of Fosamax (alendronate) in the fall of 1995 marked a paradigm shift in our approach to the treatment of women with osteoporosis. Until then, our medicine cabinet held limited choices. The options were estrogen or daily shots of a hormone called calcitonin. If push came to shove, and neither of those medicines were appropriate, I would write a prescription for Didronel (etidronate) two weeks at a time in three-month cycles. This use was “off label,” meaning Didronel was not approved by the FDA for the treatment of osteoporosis.
Back then, osteoporosis was not on the radar screen. Few women were treated for osteoporosis, even though they may have had broken bones or were stooped over due to spine fractures. Evaluation of bone health was not part of the routine care for postmenopausal women, let alone for anyone else.
At that time, the ability to measure bone density was new as well. The DXA machines were located primarily in academic or university settings. Most of them were used for research rather than for patient care. The World Health Organization (WHO) had just released the criteria for diagnosis of osteoporosis in 1994 and the concepts of T-score and Z-score were still foreign to most physicians.
The launch of Fosamax, the first bone-specific medicine by Merck, helped advance the field of bone health by leaps and bounds. Other medicines were soon to follow. We have come a long way, baby! Like anything else, the more you learn, the more you realize what you don't know. You can read summaries of the unknowns, the recent controversies, and where more research is needed in the section titled “Hot Topics: Cocktail Party Conversations” (see page 245).
Fosamax was the first kid on the block to move into the new area of bonespecific medicines. Fosamax remained on top as the market leader, even after other medicines entered the marketplace. In 2008, the patents for all pill doses of Fosamax expired, except for the liquid formulation and the one with vitamin D—”Fosamax plus D.” Now multiple manufacturers produce generic alendronate. Since generics are less expensive than the branded medicine, generic alendronates account for the most prescriptions written for treatment of osteoporosis today.
SCIENTIFIC RATIONALE
Fosamax is a bisphosphonate. It reduces the breakdown of bone without a direct effect on bone formation by interfering with the activity of the bone breakdown cells, osteoclasts.
What Is a Bisphosphonate?
Bisphosphonates are synthetic compounds of the natural phosphorus that binds to the bone mineral. The name refers to the chemical structure of these phosphorus compounds: two phosphonate groups linked by a carbon atom. The side chains attached to the carbon atom differentiate the various bisphosphonates.
Bisphosphonates block the breakdown of the bone by physically interfering with bone breakdown cells, the osteoclasts. The active osteoclasts, shown with a convoluted bottom called a ruffled border, start the bone breakdown process by attaching to the bone mineral surface. Bisphosphonates work by binding to the bone mineral surface at the locations where bone is being broken down by osteoclasts. Osteoclasts eat the bisphosphonate (BP) along with other bone breakdown products.
Once in the osteoclast, bisphosphonates (Fosamax, Actonel, Atelvia, Boniva, and Reclast) block key enzymes, and this disrupts the osteoclast's internal workings, which leads to the disappearance of its ruffled border as it becomes inactive. In this way, the bone breakdown is stopped. The bone forming cells, osteoblasts, proceed with new bone formation. The new mineralized bone covers the bisphosphonate. Ultimately, because of the coupling of the processes in bone remodeling, bone formation activity goes down as the result of the decrease in bone breakdown.
Remodeling pits that were excavated by osteoclasts before treatment are partially filled in during treatment and fewer remodeling pits are made. The net effect is an increase in bone mass and reduction in risk of fracture. Without treatment, bone loss continues with loss of microstructure.
Fosamax
(alendronate)
Category
Antiresorptive
Bisphosphonate
Manufacturer
Merck
Pivotal Fracture Trial
FIT
Fracture Reduction
Spine
Nonspine
Hip
Indications for Osteoporosis
Prevention postmenopausal women
Treatment postmenopausal women
Men
Steroid-induced treatment
Contraindications
Esophagus problems
Unable to sit or stand upright 30 minutes
Low blood calcium
Swallowing problems
Other Considerations
Stomach or digestive problems
Reduced kidney function
Possible Side Effects
Heartburn or chest pain
Swallowing difficulty
Stomach pain
Nausea
Change in bowel movements
Bone, joint, or muscle pain
Nonhealing sore in mouth or jaw
Atypical femur fracture
Doses
70 mg pill/week most common
35 mg pill/week prevention
Daily: 5 mg or 10 mg pill
Additional Information
Special dosing instructions
Fosamax plus D
Generic alendronate in 2008
EFFECTIVENESS
FIT: The Fracture Intervention Trial
This pivotal fracture study with about 6,500 postmenopausal women was planned for four years and set up as two separate studies, referred to as FIT1 and FIT2. Women were screened by bone density and spine x-rays at eleven universities. In FIT1, the women had low bone density and a spine fracture detected by x-ray. FIT2 participants had low bone density only.
Subjects either took Fosamax 5 mg or a placebo once a day. After two years, the dose was increased to 10 mg based on results of another study, which was investigating a range of doses. The following year that study also showed a robust decrease in spine fractures. Therefore, the FIT1 study was stopped to see if its high-risk participants experienced the same benefit after about three years of treatment. Fracture reduction was about 50 percent at the spine, wrist, and hip. The FIT2 study was continued as originally planned and concluded after four years.
In the FIT groups combined, fracture reduction with Fosamax was seen in women with osteoporosis at all sites:
| Spine fractures by x-ray | 48% |
| Painful spine fractures | 45% |
| Nonspine fractures | 27% |
| Hip fractures | 53% |
Other Studies
In addition to the studies for indications and different formulations, multiple other studies were performed with Fosamax. These thorough research investigations showed consistency of effect across age, both in men and women.
Ten Years of Experience
Fosamax has been studied longer than any other osteoporosis medicine in a controlled clinical trials setting. The original dose ranging study was continued for a total of ten years with around two hundred women. Treatment with 10 mg of Fosamax daily resulted in a continued gradual increase in bone density to an average of 14 percent. Bone density at the hip remained stable. The total hip bone density maintained at about 7 percent above baseline and the bone density at the femoral neck region maintained at over 5 percent above baseline. Bone turnover markers remained in the premenopausal range. No issues of safety or tolerability were seen with this length of treatment in this study population.
FLEX: Fracture Intervention Trial Long-Term Extension
The original participants in FIT who were taking actual Fosamax during the study were recruited to continue in a five-year extension of the study, called FLEX. A total of 1,100 women were reassigned by chance into three groups: placebo, Fosamax 5 mg, or Fosamax 10 mg. The purpose of the study was to see if continued treatment is required once you have already increased your bone density and decreased your risk of a fracture. If so, the researchers asked, what is the optimal dose? Those women taking 5 or 10 mg daily, by the end of the study, had used Fosamax for a total of ten years.
The study was designed to look primarily at BMD changes; because of the smaller group size, fractures were collected as adverse events. Those who switched to the placebo (the same as stopping your medicine) lost all or almost all of what they had gained in bone density over the first five years. The two groups of subjects that continued to receive Fosamax doses showed stable bone density at the hip sites. At the spine, bone density was maintained with a small increase in the placebo group, and those on Fosamax gained over five percent. At the spine, the average difference between groups was almost four percent at the end of FLEX.
Bone turnover markers showed that those continuing Fosamax maintained stable lower levels of bone turnover. Those who were no longer taking Fosamax showed a gradual rise in markers over five years. Their marker levels ended up close to the baseline measured ten years earlier. This correlated with a slow decline in bone density after stopping Fosamax. The bone density and bone marker changes showed some residual effect for at least five years after subjects had ended a five-year course of therapy. In addition, no difference in the number of fractures was seen between the group that had stopped taking Fosamax and the groups that had continued to take Fosamax.
So, should you continue Fosamax beyond five years? Well, it depends. If you are not at high risk for spine fractures and have a good response with Fosamax after five years of therapy, a “holiday” period of up to five years without therapy may be reasonable. Women who have had a spine fracture or are at high risk for one should continue treatment after five years. Reevaluate its use with your doctor every year.
SAFETY
The common adverse effects of Fosamax are different digestive complaints, including heartburn, stomach pain, and diarrhea. In the trials, the same number of subjects reported these problems in both the Fosamax and placebo groups.
Note that the generic alendronates are not made in the same way as branded Fosamax tablets, which were pressed, then coated. Therefore, the generic alendronate may tend to dissolve before reaching the stomach. Alendronate becomes an acid when it dissolves, which is fine for your stomach, but contact in your mouth or with the esophagus could lead to irritation. Be sure to drink a full glass of water to ensure the passage of the pill into the stomach.
Contact your doctor if you have heartburn or worsening heartburn while taking alendronate.
Postmarketing reports of muscle and joint pain that can be severe and non-healing sores in your mouth or jawbone (called osteonecrosis of the jaw) led the FDA to issue a warning for all bisphosphonates.
In 2010, investigation of atypical femur fractures that occur below the hip in patients on bisphosphonates was conducted by the FDA. These fractures have characteristics that are distinct from typical osteoporotic fractures. In light of the number of people treated with bisphosphonates and the few reports of these atypical fractures, their occurrence was considered rare. However, neither the actual cause of the fractures nor which individuals are at risk is known. In response to this observation, the FDA now requires that a “Medication Guide” be given to you when you pick up your prescription and additional labeling warns about these atypical fractures. The majority of patients on bisphosphonates who experienced these atypical fractures had dull aching pain in their thigh prior to fracture. Therefore, if you develop pain in your thigh or groin while taking any brand of bisphosphonates contact your doctor to have your symptom evaluated.
Bone biopsy in women who took Fosamax for ten years showed normal microstructure and mineralization. After ten years, only a small amount of Fosamax was in the bone—an estimated 70 mg.
EASE OF USE
Special instructions must be followed to ensure that the tablet reaches your stomach and that the medicine is absorbed well.
In the morning before you have anything to eat or drink, take Fosamax with a full glass of plain water. You must sit upright or stand for half an hour before eating, drinking, or taking any other medicines whatsoever.
It takes some planning but you can easily incorporate this regimen into your once-a-week schedule. Pick one day in the week that works best for you to have a more leisurely morning. Take your pill, then go for at least a thirty-minute walk. Return home and get on with your day.
What if you miss a dose? Do not take it when you think about it later in the day. You always need to wait until the next morning to take your pill. Do not take two tablets on the same day. Do not worry about missing a week; just don't make it a habit. You have to take the medicine for it to work.
Extra Tips for Taking Fosamax
(and any Bisphosphonate Pills)
Make one change at a time. Everything you do to optimize your bone health should be taken one step at a time. If you decide you need calcium supplements to boost your daily calcium to the required level, do not start calcium and your prescription medicine at the same time. Calcium can be the cause of many digestive symptoms. If you start everything all at once and develop constipation, for instance, you will not be able to pinpoint the cause. By making one addition at a time, you will have a better idea, if a symptom arises, what might have been the culprit and what needs to be modified.
Limit the amount of water to 6 to 8 ounces. Some of my patients thought more was better. They drank two or three full glasses, thinking it would lessen their chance for problems. However, water is a good laxative, and looser bowel movements or diarrhea sometimes resulted. If you have a tendency for reflux, the extra liquid may increase the chances of heartburn.
Consider taking a heartburn medicine the night before. If you have experienced a little bit of heartburn or indigestion on the day you take your pill, decreasing the acid in your stomach may help. The night before you take your pill, take a heartburn medicine such as Prilosec® or Prevacid® to see if decreasing acid production eliminates your symptoms. As an added bonus, the absorption of your medicine may be enhanced. Studies of the action of the medicines show a small improvement in absorption with a dose of heartburn medicine.
WHAT SHOULD I EXPECT?
Check back with your doctor after a month to let him know that you are taking the tablets in the prescribed way and that you have no side effects. If you do develop any side effects, contact your doctor in a timely fashion. Since each bisphosphonate is different, you may not have the same problem with another one.
In the pivotal fracture trial, after two years of treatment with Fosamax, the average bone mineral density increases were:
| Lumbar spine: | 7% |
| Total hip: | 3.5% |
| Femoral neck: | 27% |
| Hip fractures (neck region of hip) |
3% |
Changes observed on your first follow-up DXA at two years may differ; improvement in BMD or no change are both considered positive response to therapy.
FINAL NOTES
At least a dozen manufacturers supply generic alendronates. Pay close attention to each refill of your prescription. The generic pill may not be from the same manufacturer. Your pharmacy or healthcare plan may change supplier based on best costs. Each time, make sure you are tolerating the “new” tablet.
The prevention dose—35 mg once a week—is half of the treatment dose. Also, this is the dose tested and approved for premenopausal women or men taking long-term steroids.
One other formulation is also available. “Fosamax plus D” incorporates 70 mg of Fosamax with vitamin D3 in the same tablet for once-a-week use. Fosamax plus D is available with two different doses of vitamin D3, either 2,800 IU or 5,600 IU. It is a way to get branded Fosamax with a weekly dose of vitamin D. An oral solution of Fosamax was previously available but manufacturing of this product was stopped in early 2011.
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The Bare Bones
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Actonel: Me, Too?
As number two on the scene in the bisphosphonate class, Actonel (risedronate) was placed in the position of always trying harder. Picture the classic Avis versus Hertz battle. Actonel is the “We Try Harder” product. The challenge is how do you differentiate yourself from number one? Is Actonel the same as Fosamax, or is it something different?
Actonel is different. Bisphosphonates share many common properties. However, the different chemical structure of each medicine in this class gives each one distinct properties.
Serendipity: From Water Softeners to Medicine for Bone Problems
How did Procter & Gamble (P&G), a household products company, maker of Tide®, Crest®, and Bounty®, end up in the pharmaceutical business? Their research scientists' discoveries took them down an unexpected path. In the 1960s, they were designing additives in an attempt to eliminate that pesky soap scum ring around your bathtub. These organic phosphorus compounds, diphosphonates, adhered to the calcium and magnesium in hard water. The name was corrected later to bisphosphonates to accurately reflect their chemical structure.
The physiologic properties of bisphosphonates led their research into the dental arena, where they had years of experience with Crest toothpaste. Their work on the prevention of cavities and tartar build-up provided the basis for experiments with bisphosphonates. The bisphosphonate blocked the formation of tartar by forming a surface film that protected the tooth enamel.
These studies on teeth provided much of the background for subsequent research on the phosphonates with hydroxyapatite, the major constituent of bone, which undergoes similar surface reactions as tooth enamel.
At the same time, Dr. Herbert Fleisch and his colleagues at the University of Berne in Switzerland were studying various phosphonates for use in blocking calcification. A chance meeting brought Dr. Fleisch and the researchers from P&G together. A merger of research pathways led to the discovery that bisphosphonates have a direct effect on calcium and bone metabolism. Their first paper was published in Science in 1969, which serves as the date of the beginning of bisphosphonate use for bone problems.
Animal experiments showed that bisphosphonates blocked bone loss by decreasing bone turnover. The first clinical trials were done in patients with Paget's disease, who have areas of increased bone turnover. The agent was etidronate (Didronel). It was effective also in lowering blood calcium and bone turnover in multiple myeloma (cancer of the bone) and other cancers.
Osteoporosis was studied subsequently in the first multicenter trial of postmenopausal women. This clinical trial was responsible indirectly for my career focus on osteoporosis. In conferences leading up to the start of the trial at Emory University, endocrinologist Dr. Nelson Watts taught me about “postmenopausal osteoporosis.” That first exposure as a junior resident piqued my interest in bone health that has never stopped. Despite initial promising results, Didronel was never approved for treatment of osteoporosis in the United States.
Actonel was P&G's second medicine in the bisphosphonate class tested for osteoporosis. In 2009, the fortieth anniversary year of bisphosphonates, P&G sold Actonel and its prescription medicine enterprise to the Irish company Warner Chilcott.
SCIENTIFIC RATIONALE
Actonel is a bisphosphonate. Its mode of action is the same as Fosamax. It blocks the breakdown of the bone by interfering with the activity of osteoclasts. Actonel does not bind as strongly to the bone. When you stop Actonel, your bone will rev up its machinery back to full steam more quickly than after stopping Fosamax. It takes about twelve months to increase bone turnover after stopping Actonel in contrast to about two to three years for Fosamax.
Actonel
(risedronate)
Category
Antiresorptive
Bisphosphonate
Manufacturer
Warner Chilcott
(Procter & Gamble initially)
Pivotal Fracture Trial
VERT
Fracture Reduction
Spine
Nonspine
Hip
Indications for Osteoporosis
Prevention postmenopausal women
Treatment postmenopausal women
Men
Steroid-induced prevention
Steroid-induced treatment
Contraindications
Esophagus problems
Unable to sit or stand upright 30 minutes
Low blood calcium
Other Considerations
Stomach or digestive problems
Reduced kidney function
Possible Side Effects
Heartburn or chest pain
Swallowing difficulty
Stomach pain
Nausea
Change in bowel movements
Bone, joint, or muscle pain
Flu-like symptoms (monthly dose)
Nonhealing sore in mouth or jaw
Atypical femur fracture
Doses
35 mg pill/week most common OR
150 mg pill once a month
Daily: 5 mg pill
Additional Information
Special dosing instructions
Atelvia: delayed-release 35 mg tablet of risedronate taken after breakfast once a week
EFFECTIVENESS
In the laboratory experiments, Actonel looked more potent than Fosamax. However, for effectiveness in reducing the risk of fractures in postmenopausal women, the two drugs turned out to be similar at reducing spine fractures in part due to the doses chosen.
VERT: Vertebral Efficacy with Risedronate Therapy
The pivotal fracture trial was conducted in the United States, Canada, Europe, Australia, and New Zealand. It was designed and conducted as two separate studies: “North America” and “Multinational.” As entry criteria for both studies, subjects were all postmenopausal women who had at least two spine fractures or one spine fracture with low spine bone density. However, it turns out on review of original x-rays that 20 percent of the women in the North American study did not have any spine fractures.
Two dosages of Actonel, 2.5 and 5 mg, were used versus a placebo group taking an identical looking “dummy” pill. Everyone took 1,000 mg of calcium daily. Those with low vitamin D received up to 500 IU each day. After one year, the 2.5 mg dose group was discontinued in the North American study and about 1,000 women completed the three years of study with the 5 mg pill versus placebo.
The North American fracture results at the end of three years for subjects using 5 mg daily of Actonel showed fracture reduction for:
| Spine identified by x-ray | 41% |
| Nonspine fractures | 39% |
| Hip fractures | too few fractures to show any difference |
HIP: Hip Intervention Program
In contrast to the previous osteoporosis fracture trials, which focused primarily on the spine, the objective of this study was to evaluate drug effectiveness for hip fracture reduction. Although spine fractures are the most common fractures after menopause, hip fractures are the most devastating. Because of the fewer number of hip fractures expected, a large number of women who were older and at higher risk of fracture were recruited to be part of the study. Over nine thousand women over age seventy were part of this Herculean effort to investigate the effect of Actonel on hip fractures.
Women in the seventy to seventy-nine age group were screened with a DXA for entry into the study. Women eighty and older were eligible based on risk factors alone. Only a small number of women who did not have risk factors had a DXA scan as part of their evaluation. At the end of two years, the results were surprising. The women eighty and older did not have a reduction in hip fractures. The younger group in their seventies had a 40 percent reduction in hip fractures. Putting all ages together, the overall reduction was 30 percent.
Why was a difference seen in the results between age groups? You would expect the older women to have even more benefit with treatment. However, it was not known whether the eighty-plus group actually had osteoporosis, since they did not have their bone density measured. Lesson: If you are going to receive treatment for osteoporosis, make sure you have it! You cannot use risk factors alone. If you are older, you need a bone density in addition to consideration of your risk factors, especially falls.
SAFETY
Digestive system complaints are reported for all bisphosphonates taken as pills. Nausea, heartburn, diarrhea, or constipation occurred in 10 to 13 percent of Actonel study subjects. However, there was no difference between the women taking the actual Actonel pills and those taking the inactive placebo pills.
The big question was whether Actonel was better tolerated than Fosamax in terms of digestive symptoms. In the Fosamax trials, fewer participants reported symptoms but women were not eligible if they had digestive problems. A lot of advertising dollars have been spent trying to convince you that one might be better tolerated than the other.
The reality is that you cannot predict whether you are going to have problems with one medicine versus the other. The important point is that the majority of patients have no problems with taking these medicines. They are all well tolerated. However, you need to be fastidious in following the dosing directions. Be aware of the possible side effects and contact your doctor if you have heartburn, worsening heartburn, or pain while taking Actonel.
The FDA issued a warning about muscle and joint pain that can be severe for all bisphosphonates (Actonel, Fosamax, Boniva, and Reclast) based on postmarketing reports. In addition, a warning about problems with nonhealing sores in the mouth or jawbone (osteonecrosis of jaw) was added to all bisphosphonate labeling.
You will receive a “Medication Guide” with each prescription of Actonel or Atelvia. This applies to all bisphosphonates and is required by the FDA in response to concerns about rare femur fractures that may occur below the hip in individuals taking this type of medicine.
Safety with long-term use is a hot topic. Read more about this in the section titled “Hot Topics: Cocktail Party Conversations” (see page 245).
EASE OF USE
You now have a choice of taking your Actonel weekly or monthly. You can choose 35 mg of Actonel once a week or 150 mg once a month. In addition, with the 2010 release of a 35 mg, delayed-release formulation called Atelvia, you have another option.
Special instructions must be followed to ensure that the Actonel tablet reaches your stomach and that the medicine is absorbed.
In the morning, before you have anything to eat or drink, take Actonel with a full glass of water. Then you must sit or stand upright for half an hour before eating, drinking, or taking any other medicines whatsoever.
In contrast, the extended-release risedronate called Atelvia is taken right after breakfast with at least four ounces of water. Again, you must stay upright for at least thirty minutes.
If you forget to take your pill, do not take it later in the day. Always wait until the next morning to take your pill. For once-a-week dosage, do not take two tablets on the same day. For the once-a-month pill, take your forgotten pill only if it is more than one week before your next scheduled dose.
WHAT SHOULD I EXPECT?
Check back with your doctor after one month to let him know you are taking the tablets in the right way and that you have no side effects. If you do develop side effects, report them in a timely fashion. You may not have the same problem with one of the other bisphosphonates. Sometimes you have to do trial and error to see which one works best for you.
In the pivotal fracture trial, after two years of treatment with Actonel, the average bone mineral density increases were:
| Lumbar Spine: | 5% |
| Total hip: | 3% |
| Femoral neck: (neck region of hip) |
2% |
Changes observed on your first follow-up DXA at two years may differ; improvement in BMD or no changes are both considered positive response to therapy.
FINAL NOTES
Two two-year extensions of the pivotal fracture trial with several hundred women showed continued effectiveness in increasing bone density by using Actonel for a total of seven years in a clinical trial setting. Side effects remained low and were similar to the placebo group.
The prevention dose is the same as the treatment dose (35 mg once a week). Also, Actonel is approved for both prevention and treatment of premenopausal women or men taking long-term steroids. Atelvia is approved for treatment of postmenopausal women with osteoporosis.
Procter & Gamble sold Actonel to the Irish company Warner and Chilcott in 2009. The patent on Actonel expires in 2014.
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The Bare Bones
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Boniva: “The Sally Field Drug”
Prior to a few years ago, mention of the name Sally Field probably brought to mind fond memories of Gidget, the Flying Nun, or even Forrest Gump's mother. If you watch any television, you've probably seen her as the celebrity pitchwoman for an osteoporosis medicine. Academy Award-winning actress Sally Field's promotion of Boniva (ibandronate) has been extremely effective consumer marketing.
Prior to the release of the medicine, I sat on consultant boards with other experts, and the concern was that Boniva only showed effectiveness in reducing fracture risk at the spine. Although it was in the same class as Fosamax and Actonel, it did not show similar fracture effectiveness at the other common sites of osteoporotic fractures. Enter Madison Avenue. A television advertising campaign with Ms. Field, combined with eye-catching print ads, propelled its visibility. It was not long before women walked into their doctors' offices and asked about the “Sally Field drug.”
With all due respect to the glitzy ad campaign, what made Boniva an attractive choice over Fosamax and Actonel was the fact that you took it just once a month. Only twelve tablets required all year made it the easy choice. Now that Actonel has a once-a-month product, Boniva no longer has a competitive dosing advantage.
SCIENTIFIC RATIONALE
Boniva is a bisphosphonate in the same class as Fosamax, Actonel, Atelvia, and Reclast. All bisphosphonates have a similar action. They attach to the bone and block its breakdown by interfering with the activity of osteoclasts.
Boniva
(ibandronate)
Category
Antiresorptive
Bisphosphonate
Manufacturer
Genentech, part of the Roche Group
Pivotal Fracture Trial
BONE
Fracture Reduction
Spine only
Indications for Osteoporosis
Prevention postmenopausal women
Treatment postmenopausal women
Contraindications
Esophagus problems
Unable to sit or stand upright 60 minutes
Low blood calcium
Swallowing problems
Other Considerations
Stomach or digestive problems
Reduced kidney function
Possible Side Effects
Heartburn or chest pain
Swallowing difficulty
Stomach pain
Diarrhea
Back pain
Bone, joint, or muscle pain
Flu-like symptoms with first doses
Nonhealing sore in mouth or jaw
Atypical femur fracture
Doses
150 mg pill once a month
3 mg injection by vein every 3 months
Additional Information
Special dosing instructions
Note: 60 minute wait required after pill before eating or drinking
EFFECTIVENESS
BONE: Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe
About three thousand women with postmenopausal osteoporosis were divided equally among three groups: Boniva 2.5 mg pill every day, Boniva 20 mg pill intermittent dose, or dummy placebo pill. The intermittent dose of 20 mg every other day for twelve doses every three months provided a similar total dose to the daily 2.5 mg regimen. The goal was to see if Boniva given in a less frequent,intermittent dosing schedule would reduce the risk of fractures. The subjects were at high risk for spine fractures, since by x-ray all the women had at least one spine fracture and 40 percent had two or more spine fractures.
At the end of three years, women taking either form of Boniva had fracture reduction only at the spine:
| Spine fractures on x-ray | 52% |
| Painful spine fractures | 49% |
| Nonspine fractures | no reduction |
| Hip fractures | no reduction |
No reduction was seen in nonspine fractures, with a similar number of fractures occurring in each group. The number of fractures reported at individual nonspine sites, including the hip, wrist, leg, pelvis, and ribs, were the same for those taking Boniva and those taking placebo pills. Boniva is not as effective as the other bisphosphonates in lowering the risk of all types of fractures.
A further analysis performed after the initial analysis showed fracture benefit at nonspine sites in a smaller group of study subjects with lower hip bone density. Higher risk women, defined by a bone density T-score of -3.0 and lower at the femoral neck, had decreased risk of nonspine fracture. If you fit that bone density profile, Boniva will likely be an effective medicine for lowering your risk of fractures. For women with higher bone density, you may want to consider another choice of medicine.
OTHER STUDIES
MOBILE: Monthly Oral Ibandronate in Ladies
After the BONE study found that the intermittent dosing had similar fracture reduction at the spine, MOBILE investigated different dosing regimens. Four groups of four hundred postmenopausal women with osteoporosis were given either daily or different monthly doses of Boniva. After two years, women receiving Boniva 150 mg monthly had the largest bone density increases at the spine and hip.
It is important to note that the 150 mg dose is double the dose used in the BONE study, which showed fracture reduction at the spine. What is not known: Does higher bone density achieved with the higher dose translate into more effective lowering of fracture risk for nonspine and hip fractures?
DIVA Study (Dosing Intravenous Administration)
This clinical trial found that a shot into the vein, called an intravenous (IV) injection, of 2 mg of Boniva every two months and 3 mg of Boniva every three months is equivalent to the effectiveness and safety of a daily 2.5 mg dose. At two years, increases in lumbar spine bone density with intravenous administration were higher compared with the daily oral dose. The FDA approved the intravenous regimen of 3 mg every three months.
SAFETY
As with other bisphosphonates, about one in ten subjects complained of heartburn, but fewer complained of stomach pain, nausea, and vomiting. Similar numbers of study subjects reported these problems regardless of whether they were in Boniva or placebo groups. Contact your doctor if you have heartburn or worsening heartburn while taking Boniva.
The once-a-month dose is more likely to involve flu-like symptoms than more frequent dosing regimens. About one in eleven may experience this side effect, called an “acute phase reaction,” which occurs within three days of taking Boniva.
Postmarketing reports of jawbone problems and muscle and joint pain that can be severe led the FDA to issue a warning for all bisphosphonates. In addition, you will receive a “Medication Guide” with each prescription or administration of Boniva. This applies to all bisphosphonates and is required by the FDA in response to concerns about rare femur fractures that may occur below the hip in individuals taking this class of medicines.
EASE OF USE
Boniva fits the bill. You only need to think about it once a month. Don't forget! Boniva literature encourages you to designate a “Boniva Day” to help you remember. Mark your calendar.
The special instructions below must be followed to ensure that the tablet reaches your stomach and the medicine is well absorbed.
Take the tablet with a full glass of water in the morning before you eat, drink, or take other medicines. You must wait one hour, a full 60 minutes, after taking the pill before you can eat or drink or take any other pill of any kind. You must remain upright during the whole hour. (Note: This is double the time of dosing regimen for Fosamax and Actonel.) Remember, this includes lying down to do your exercise stretches—don't do them until sixty minutes have passed. It is a good time for a nice, long, morning walk.
What if you miss a dose? Do not take it when you think about it later in the day. Wait until the morning of the next day. Take your forgotten pill only if it is more than seven days before your next scheduled dose.
WHAT SHOULD I EXPECT?
Check back with your doctor after your first dose to let him know that you are taking the tablets in the prescribed way and that you have not had any problems. If you do develop any side effects, you may not have the same problem with one of the other bisphosphonate pills. Talk with your doctor about your options.
In a clinical trial (MOBILE) after two years of treatment with Boniva 150 mg once a month, the average bone mineral density increases were:
| Lumbar spine: | 6% |
| Total hip: | 4% |
| Femoral neck: (neck region of hip) |
3% |
Changes observed on your first follow-up DXA at two years may differ; improvement in BMD or no changes are both considered positive response to therapy.
FINAL NOTES
Boniva is approved for prevention and treatment of postmenopausal osteoporosis. It has no other indications. An intravenous formulation is reserved usually for women who are unable to stand or sit upright for sixty minutes, are unable to tolerate pills, or have esophageal or stomach problems.
Boniva's patent expires March 2012 unless legal challenges hold off generic equivalents awhile longer.
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The Bare Bones
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Reclast: Just Once a Year
Once a year! How can that be possible? The other medicines in the same class, bisphosphonates, were all tested in fracture trials with a once-a-day regimen, and Boniva stretched out the interval dosing to three months. How can a “relative” possibly be so different? If you think of your own relatives, you understand right away! You only need to take Reclast (zoledronic acid) intermittently because this medicine is thought to “recycle” in and out of bone. In a sense, the bone is on autopilot. Also, Reclast is given only by an infusion into your vein, which takes away any worries about absorption of medicine or digestive problems. Some people are not good about taking their medicine; this dosing method ensures that you get the medicine.
SCIENTIFIC RATIONALE
Reclast is a bisphosphonate. Its mode of action is the same as bisphosphonates in pill form. You may refer to the diagram in the Fosamax section to see its effect on the osteoclast activity. Reclast binds strongly to the bone and may later be released to recycle.
Reclast
(zoledronic acid)
Category
Antiresorptive
Bisphosphonate
Manufacturer
Novartis
Pivotal Fracture Trial
HORIZON
Fracture Reduction
Spine
Nonspine
Hip
Indications for Osteoporosis
Treatment postmenopausal women
Prevention postmenopausal women
Men
Steroid-induced prevention
Steroid-induced treatment
Contraindications
Low blood calcium
Other Considerations
Reduced kidney function
Blood test for creatinine should be checked before each dose
Caution if aspirin-sensitive
Possible Side Effects
Fever, headache and flu-like symptoms within 3 days after dose
Nausea
Diarrhea
Bone, joint, or muscle pain
Nonhealing sore in mouth or jaw
Atypical femur fracture
Doses
5 mg given by infusion in your vein once a year
Prevention dose 5 mg every 2 years
Additional Information
Taking 2 acetaminophen (Tylenol®) before the infusion may decrease flu-like symptoms
Drink plenty of water the day before and 2 glasses before dose
Zometa® is same medicine; don't take both
EFFECTIVENESS
HORIZON PFT: Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly, Pivotal Fracture Trial
This pivotal fracture trial investigated once-yearly infusion of Reclast 5 mg in 7,700 postmenopausal women with osteoporosis. The criteria for entry in this study were designed to create a “real world” situation that included women who had taken similar medicines. Therefore, most of the women had been on osteoporosis treatment and one-fifth of the women also continued taking their regular osteoporosis medicines (not other bisphosphonates or Forteo) during the study. Their average age of seventy-three was a little older than the average age of subjects in other fracture trials. About two-thirds of all participants started the study with one or more spine fractures.
After three years, potent fracture reduction was seen for all sites:
| Spine fractures by x-ray | 70% |
| Painful spine fractures | 77% |
| Nonspine fractures | 25% |
| Hip fractures | 41% |
HORIZON Recurrent Fracture Trial: Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Recurrent Fracture Trial
The Horizon Recurrent Fracture Trial was completely different from any previous fracture study. All 2,100 men and women had a recent hip fracture. With the increased risk of another fracture, would these high-risk patients benefit from treatment? This study set out to prove what we have been “preaching”—treat to prevent the next fracture. Within ninety days of their hip fracture, participants received an infusion of either Reclast or placebo and the infusions were repeated at one-year intervals.
Rather than a set time frame, the end of this study occurred when a preset number of fractures occurred. The study lasted almost two years. Total fractures were reduced by 35 percent and painful spine fractures were reduced by about half. Spine x-rays were not done.
The exciting results of the study went beyond the fracture reduction, which was impressive in itself. The number of deaths was lower in the Reclast group; their death rate was 28 percent lower. This is a first for any study on bone, and it is an important result. Though the “why” has not been determined, the Reclast group had fewer deaths due to pneumonia and irregular heart rhythms. These observations suggest that Reclast may have immune or anti-inflammatory effects that explain the observed improved survival.
Reclast, given any time two to twelve weeks after hip fracture, showed effectiveness in decreasing risk of fracture and death. Therefore, this is the time interval after hip fracture for administration of Reclast to achieve results similar to this study.
SAFETY
Since all bisphosphonates are eliminated through the kidney, it is important to know your kidney function. A blood test for creatinine, which is a measure of your kidney function, should be checked before each annual dose is given. Be sure you stay well hydrated. You should drink plenty of water the day or two prior to your infusion. Drinking a couple glasses of water before your infusion is also recommended.
Since the medicine is given by vein, you do not need to worry about irritation of the esophagus or stomach. The infusion of Reclast can cause flu-like symptoms with fever and muscle aches within the first seventy-two hours after receiving the medicine. In the hip fracture study, two acetaminophen (Tylenol) were given to try to prevent those symptoms. Only one in fourteen subjects had fever. You may need a few additional doses of acetaminophen if you have any symptoms. Compared with the first infusion, there is usually a reduction in these side effects during subsequent infusions.
Like the other bisphosphonates, Reclast has an FDA warning about postmarketing reports of muscle and joint pain that can be severe and jawbone problems. The higher potency of this medicine may pose a greater risk for jawbone problems. However, cases of osteonecrosis of the jaw were not reported in the fracture trials. On review of the HORIZON PFT data, two possible cases were found: one woman on Reclast, the other on placebo.
You will be given a “Medication Guide” each time you receive Reclast. Atypical femur fractures that occur below the hip in patients on bisphosphonates are rare. Neither the cause nor the risk factors have been established. If you develop pain in your thigh or groin contact your doctor to have your symptom evaluated. The majority of patients had dull aching pain in their thigh prior to this type of fracture.
A type of irregular heart rhythm called atrial fibrillation happened more often in women taking Reclast in HORIZON PFT. On a close examination of these cases, it turns out that the numbers reporting atrial fibrillation were constant in the Reclast group, but fewer subjects in the placebo group reported the problem in the third year. When the comparison was done, it appeared that atrial fibrillation increased in the Reclast group, but the higher relative percentage was actually due to fewer cases in the placebo group.
EASE OF USE
You take care of everything in just one day a year, though the infusion requires some coordination and logistics. Your doctor may refer you to either an infusion center or the hospital to receive your medicine. The actual duration of the infusion is less than half an hour. You will be checked in and then an IV will be started. A small amount of liquid containing the medicine is given to you by vein over fifteen to thirty minutes. Count on an hour or so of total time.
WHAT SHOULD I EXPECT?
In the pivotal fracture trial, after two years of treatment with Reclast, the average bone mineral density increases were:
| Lumbar spine: | 6% |
| Total hip: | 4% |
| Femoral neck: (neck region of hip) |
3% |
Changes observed on your first follow-up DXA at two years may differ; improvement in BMD or no change are both considered positive response to therapy.
FINAL NOTES
Reclast is also approved for prevention of osteoporosis. The dose is the same but the interval for use is extended to two years. Reclast is approved for treatment in men with osteoporosis and for prevention and treatment in men and women taking steroids.
Cancer patients are sometimes prescribed the same medicine in a lower dose under a different name, Zometa, which should not be taken with Reclast.
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The Bare Bones
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Estrogens: Effects on Bone
In 2002, the results of the Women's Health Initiative (WHI) rocked our beliefs about estrogen. The use of the combination of estrogen and progesterone in the form of Prempro® showed more harm than good. The increased risk of breast cancer, heart attack, stroke, and blood clots outweighed the lower risk of colon cancer and reduction in fractures.
Overnight, estrogen went from the status of “favored child” to being disinherited. As a result, the use of estrogens changed dramatically.
For bone health, estrogen was moved to the prevention of postmenopausal osteoporosis category only. The additional caveat in the indications specifies that it is not a “first choice” for prevention. Estrogen should be considered only if you are unable to use other nonestrogen medicines.
Estrogen dropped out of the medicine chest as a mainstay of treatment for osteoporosis even though it is bone protective. Its other problems overshadowed its bone benefits. One outcome of the fallout from WHI was investigation of other doses and formulations of estrogens. We now know that quite low doses appear to prevent bone loss, but the effects of lower doses on breast cancer, heart disease, and stroke, are not known.
SCIENTIFIC RATIONALE
Estrogen therapy blocks the breakdown of bone by the osteoclasts. It also restores the estrogen support of bone remodeling that is lost with the transition to menopause. This form of therapy restores an approximate balance between breakdown of bone and formation of bone so that stable bone mass is maintained.
Estrogens
(multiple brands)
Category
Antiresorptive
Estrogens
Manufacturer
Multiple
Pivotal Fracture Trial
(WHI)
Fracture Reduction
Spine
Nonspine
Hip
Indications for Osteoporosis
Prevention postmenopausal women
Contraindications
Genital bleeding
History of clotting problems in deep veins of legs, lung, or eye
Recent heart attack or stroke
History of breast cancer
Other Considerations
Black box warning: risk of heart attack, stroke, clotting in deep veins of legs, lungs, or eyes; endometrial and breast cancer; memory problems
Gallbladder disease
Elevated blood pressure
Abnormal liver function
High triglycerides
Possible Side Effects
Breakthrough bleeding
Breast tenderness
Ankle swelling (edema)
Joint pain
Headache
Dose
Multiple formulations and doses
Additional Information
Use with progesterone to protect lining of womb (uterus)
Bone loss accelerates with stopping
EFFECTIVENESS
Although estrogen was used for years for the treatment of osteoporosis, there was no formal pivotal fracture trial to show its effectiveness. The evidence was observational and from smaller clinical trials. Women who took estrogen were observed to have fewer fractures when compared with women who did not take estrogen.
WHI: Women's Health Initiative
Fractures were assessed as one of the outcomes in two large estrogen trials, combination estrogen plus progesterone (Prempro) and estrogen alone (Premarin® 0.625 mg daily).
After an average of 5.6 years, women in the combination study had fewer fractures. One-third fewer hip fractures and clinical spine fractures were recorded in the Prempro users. In contrast to the bone-specific trials, spine x-rays were not taken and bone density DXA scans were done only in a small percentage of the participants at three of the forty study sites.
Below are the fracture reduction results after five years of use of a combination of estrogen and progesterone given as Pempro:
| Painful spine fractures | 35% |
| Hip fractures | 33% |
| Wrist fractures | 29% |
| All fractures | 24% |
In the estrogen-alone study, the fracture reduction was similar after an average of seven years of use.
SAFETY
The list of safety issues has grown over the years with the results of the WHI and other large clinical trials using estrogen. A “black box warning” in the package insert for estrogens includes multiple risks, which are highlighted in the summary box.
Are You at Risk for Clotting Problems?
Clotting problems are associated with using both estrogens and the “designer estrogen” Evista®. Do not overlook these potential problems. You may see several terms and abbreviations that refer to clotting problems. The general term for clotting problems is venous thromboembolism (VTE). A clot within a blood vessel is a thrombus. If a piece of the thrombus breaks off and travels to block a blood vessel, thereby cutting off the blood supply to the vessel's destination, that is an embolism. A clotting problem in the deep veins of the legs is called deep vein thrombosis (DVT). A pulmonary embolism (PE) occurs when a clot breaks off and travels to the lung, blocking part of its blood supply. This is a dangerous event.
Not everyone is at equal risk. It is important to understand your risk if you are considering using estrogens or Evista. Following are the general risk factors associated with clotting problems.
Racial Differences. In order of risk: African Americans, Caucasians, Hispanics, and Asians. African Americans are at highest risk, while Asians, at the other end of the spectrum, are at low risk. In addition, African Americans are more likely to suffer the more serious and life-threatening pulmonary embolism.
Age. Your risk increases with age. The older you are, the less likely estrogen is going to be a choice for you.
Family History. About 5 percent of Caucasian women of European ancestry have genetic mutations that make blood tend to clot more easily. (This trait may have evolved to help in surviving childbirth, but it may prove troublesome in later life.) DNA testing is the only way to know for sure whether you have this genetic mutation. Short of DNA testing, the best guide is family history. If someone in your family has had clots, you are at higher risk.
Lifestyle. Think cardiac risk factors: high blood pressure, high cholesterol, and obesity are also factors for increased risk of clotting. This is the main reason African Americans are thought to have higher rates. Some research suggests that using cholesterol-lowering medicines lowers your risk. If you have cardiac risk factors, choose a different type of medicine.
Pill versus Patch. Oral estrogen pills are processed by the liver, so factors that promote clotting may be increased. The patch and gels are absorbed through the skin and bypass the liver. Clotting problems are associated with pills, not patches or skin preparations.
EASE OF USE
Estrogens come in multiple forms and dosages. The lowest dose possible for symptom relief is recommended.
WHAT SHOULD I EXPECT?
Changes are dependent on the dosage of estrogen. You may repeat your bone density after two years of therapy, but don't expect much change if you are on the lower doses. Estrogen, as indicated for prevention, basically maintains your bone mass.
In a clinical trial using the lowest dose estradiol patch (Menostar® patch, which delivers 14 micrograms of estradiol a day) for two years, average bone mineral density changes were:
| Lumbar spine: | 2.6% improvement |
| Total hip: | stable no change |
| Femoral neck: (neck region of hip) |
stable no change |
Changes observed on your first follow-up DXA at two years may differ; improvement in BMD or no change are both considered positive response to therapy. Higher doses may yield better results, but you will want to take the lowest dose possible and avoid long-term use.
FINAL NOTES
Stopping your estrogen therapy will shift bone turnover to overdrive. When estrogen levels drop, the bone-loss machinery revs up just as though you are starting menopause. So-called catch-up loss occurs.
In the large observational National Osteoporosis Risk Assessment (NORA) study, women had an increased risk of fracture after stopping their estrogen therapy. This occurs because bone loss resumes at a faster rate when estrogen therapy is discontinued. High bone turnover is a risk factor for fractures. Plan ahead for measures that will decrease your risk. Consider another bone-active medicine to prevent the accelerated bone loss and higher risk of fracture.
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The Bare Bones
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Evista:
The Designer Estrogen or “SERM”
You may have noticed that the long titles of clinical trials are often shortened by the use of acronyms. These shortened names, as with nicknames, are used many times without referencing or knowing the full name. Therefore, using an acronym that embodies information about the study is key. In an initial steering committee meeting for the Evista® (raloxifene) fracture trial, a contest to name the study was announced; a bottle of champagne was the prize.
I took a stab at the challenge with a couple of names. At that point, the study drug was known as raloxifene; the brand name was coined later. One of my submissions, ROSE, for Raloxifene Osteoporosis Study Effects, was the top vote getter. Yeah! I was imagining the ease of designing a logo and all the other uses of roses.
A few weeks later, my bubble was burst when the study name was announced as MORE, for the Multiple Outcomes of Raloxifene Evaluation. The reason for the selection turned out to be quite clear, when you consider what raloxifene is. Raloxifene/Evista is a Selective Estrogen Receptor Modulator—”SERM”—and can also be called an Estrogen Agonist/Antagonist—“EAA.” It has a split personality. In some tissues, it works like estrogen; in others, it has the opposite effect. The potential of raloxifene/Evista for action at estrogen receptors throughout the body is immense and it effects more than just the bone.
Great name and reasoning, but I still thought I had won the contest—after all, my proposed name received the most number of votes. Eventually, I did receive the champagne—a nice bottle of Dom Pérignon®!
Evista: Given a Second Chance
Evista started its life as an anti-breast-cancer compound called keoxifene. It was developed as a medicine to compete with tamoxifen (brand name Nolvadex®, which was approved in 1977). Tamoxifen was the standard of care for postmenopausal women with breast cancer who had undergone lumpectomies; it was used following surgery to decrease the chances of breast cancer coming back. In preclinical testing, keoxifene was found to be no better than tamoxifen and the project was shelved.
Subsequently, studies of tamoxifen showed that it increased bone density. Tamoxifen has a split personality. In the breast, it behaved as an antiestrogen, and in the bone, it looked like an estrogen with positive effects. Eli Lilly and Company's scientists wondered, “Will our similar compound collecting dust on a shelf do that, too?”
Keoxifene was dusted off and rechristened “raloxifene,” which we now know by its brand name, Evista. The investigation of Evista‘s bone effects was positive and the drug development of Evista proceeded.
During the pivotal fracture trial, women on Evista had a 90 percent lower risk of breast cancer. Investigator Dr. Steven Cummings, from the University of California, San Francisco, persuaded Eli Lilly and Company to continue a study with the same women to look further at the breast cancer benefit. In addition, another study compared Evista with tamoxifen in women at high risk for breast cancer. In 2007, ten years after its initial approval for treatment of postmenopausal osteoporosis, Evista received approval both for use in reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and for use by postmenopausal women at high risk for invasive breast cancer.
SCIENTIFIC RATIONALE
Evista is an antiresorptive, which puts it in the same category as bisphosphonates. It works by mimicking the action of estrogen on the bone to decrease the action of the bone breakdown cells, the osteoclasts. However, it is not as potent as estrogen itself. Evista has a modest effect on bone metabolism. The bone turnover markers decrease about 30 percent compared with the 60 to 70 percent decline observed with bisphosphonates.
Evista
(raloxifene)
Category
Antiresorptive
Selective Estrogen Receptor Modulator (SERM) also known as an
Estrogen Agonist/Antagonist (EAA)
Manufacturer
Eli Lilly and Company
Pivotal Fracture Trial
MORE
Fracture Reduction
Spine
Indications for Osteoporosis
Treatment postmenopausal women
Prevention postmenopausal women
Contraindications
Clotting problems in deep veins of legs, lung, or eye
Other Considerations
Black box warning: risk of clotting
Fatal strokes in women with or at risk for heart attack
Breast cancer survivor
Don't take if you are on estrogen therapy
Possible Side Effects
Hot flashes
Leg cramps
Ankle swelling (edema)
Joint pain
Flu symptoms
Dose
60 mg pill once a day
Additional Information
Lowers risk of invasive breast cancer
Stop three days before long plane flight or hospitalization to decrease the chance of clotting problems
EFFECTIVENESS
MORE: Multiple Outcomes of Raloxifene Evaluation
For the pivotal fracture trial, a total of 7,700 postmenopausal women were enrolled in a three-year trial. Approximately half of the women had spine fractures identified by x-ray at the beginning of the study, and the other half had bone density in the osteoporosis range. Two doses of Evista were used; a 60 mg group and a 120 mg group were compared with a placebo group. Ultimately, only the daily 60 mg dose was approved by the FDA. For this reason, all results discussed in this section are based on this dosing regime.
The fracture results after three years of treatment with Evista 60 mg a day showed spine effectiveness only:
| Spine fractures by x-ray: | 50% reduction in women with osteoporosis by bone density only |
| 30% reduction in women with spine fractures at baseline |
|
| Painful spine fractures: | 41% |
| Nonspine fractures: | No reduction |
| Hip fractures: | No reduction |
The placebo group in this study is instructive for the natural history of high-risk women with spine fractures. The study recruitment was done before the approval of Fosamax. At the time, the only choices were estrogen and calcitonin by injection. Even at that time, many women did not want to take estrogen. The placebo group received the standard of care at the time—calcium and vitamin D supplements along with the study pill. Because they had received a bone density test and were participating in an osteoporosis study, they increased their awareness about osteoporosis. They were doing everything possible to improve their bone health.
The majority of women did not know they had a fracture because their fractures had occurred without pain. The spine fractures were identified by x-rays at entry and at each annual study visit. Twenty-one percent of the placebo group fractured another spine level in that short three-year time frame: not good.
CORE: Continuing Outcomes Relevant to Evista Study
With continued use of Evista, the hope was that fracture reduction would be seen in nonspine sites including the hip. The additional four years did not show fracture protection beyond the spine. The numbers of nonspine fractures were similar in the Evista and placebo groups. However, it did demonstrate continued reduction of breast cancer.
Other Studies
Several other large studies investigated other potential health benefits of Evista. The Study of Tamoxifen and Raloxifene (STAR) trial showed that Evista was equivalent to Tamoxifen in lowering the risk of breast cancer in women at higher risk but with fewer side effects. The Raloxifene Use for the Heart (RUTH) trial investigated use of Evista in lowering heart attacks in women with heart disease or risk factors for heart disease. No significant differences were found between those on Evista versus those taking a placebo.
SAFETY
The most common adverse events among women taking Evista were leg cramps that usually decreased and stopped with continued use. Hot flashes and sweats occurred in one in ten women, but they were not severe enough to result in discontinuation of the study medicine. The lining of the uterus (endometrium) was not stimulated although more polyps were reported in the Evista groups.
The clotting risks of 1 to 2 percent are comparable to those associated with estrogen therapy. Refer to the preceding section on estrogen for more on your risk of clotting problems. In 2007, the FDA added a black box warning about blood clotting problems to Evista's label. After review of the recent studies CORE, STAR, and RUTH, the risk of blood clots in the leg, lung, or eye was increased in the Evista groups. The label change included the approval of the new indications for reduction of invasive breast cancer.
EASE OF USE
Evista is a pill taken once a day. There are no special instructions.
WHAT SHOULD I EXPECT?
A repeat bone density test after two years of use is indicated; however, don't expect much of a change. Based on the expected change, you could wait longer for your repeat bone density test.
In the pivotal fracture trial, after two years of treatment with Evista, the average bone mineral density increases were.
| Lumbar spine: | 2.5% |
| Total hip: | 2% |
| Femoral neck: (neck region of hip) |
2% |
Changes observed on your first follow-up DXA at two years may differ; improvement in BMD or no change are both considered positive response to therapy.
FINAL NOTES
Small changes in bone density make a big difference in reducing risk of fracture at the spine.
If you have travel planned with a long car ride or plane trip, discontinue your pills three days beforehand to lessen risk of clotting problems in your legs. This recommendation also applies prior to any hospitalization or surgery.
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The Bare Bones
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Calcitonin—Miacalcin, Fortical:
The Nasal Sprays
Calcitonin has been an option for a long time. Shots of calcitonin, which is a compound derived from salmon, hit the marketplace in 1986 for treatment of Paget's disease. However, it was not until the nasal formulation of Miacalcin was approved in 1995, just a few months earlier than Fosamax, that it was indicated for treatment of postmenopausal osteoporosis. The use of Miacalcin has never gained traction, due to lack of effectiveness. It was suggested that use of Miacalcin may improve bone quality but this was never proven. The indication is for treatment of postmenopausal osteoporosis in women more than five years after menopause, which is beyond the period of rapid loss.
In 2005, Fortical, a recombinant version of calcitonin, was approved by the FDA based on its equivalence to Miacalcin. In the FDA review of effectiveness from the work done on Miacalcin, it was concluded that the evidence supported increases in bone density only at the spine. As a result, a label change for Miacalcin reflects a “downgrade” from prevention of spine fractures to spine bone density changes.
Despite the lack of good evidence for fracture reduction, calcitonin continues to be prescribed because it is easy to use and there are few side effects. It is used more often in the nursing home setting and some areas of the country, reflecting regional variations of practice. For instance, in a study of nursing homes in North Carolina and Arizona, 14 percent of those treated with prescription medicines for osteoporosis were receiving Miacalcin.
SCIENTIFIC RATIONALE
Calcitonin is a natural hormone produced in the cells of your thyroid gland. It contributes to calcium regulation in the bone, kidney, and intestine. In bone, calcitonin blocks bone breakdown by decreasing the number and activity of osteoclasts. The decrease in bone breakdown markers is only 12 percent, a mild reduction in comparison to the potent bisphosphonates and Prolia.
Miacalcin
(calcitonin-salmon)
Category
Antiresorptive
Biologic hormone
Manufacturer
Novartis
Pivotal Fracture Trial
PROOF
Fracture Reduction
Increase spine bone density
No fracture reduction or effect on hip bone density
Indications for Osteoporosis
Treatment for postmenopausal women five years after menopause
Contraindications
Allergy to calcitonin-salmon
Other Considerations
Lack of effectiveness
Possible Side Effects
Nasal irritation
(Nausea and irritation at injection site for shot)
Doses
Metered nasal spray 200 IU daily
Alternate nostrils each day
(available as injection 100 IU daily)
Additional Information
Generic available for nasal spray
Fortical approved based on equivalence to Miacalcin
EFFECTIVENESS
PROOF: Prevent Recurrence of Osteoporotic Fractures Study
This fracture trial was not conducted in a standard randomized, double-blind fashion. The doctors who had patients in the study saw the results of the bone density tests. This led to a high dropout rate. At the end of five years, only about half of the 1,100 participants remained in the study.
A total of three doses of the Miacalcin nasal spray were used: 100 IU, 200 IU, and 400 IU. The fracture reduction was only seen in the 200 IU dose, which was chosen for the marketed dose of Miacalcin. However, because so many women who lost bone density did not finish the study, this observation may not be valid.
The fracture reduction after five years of use of Miacalcin 200 IU was:
| Spine fractures by x-ray: | 33% |
| Nonspine fractures: | no reduction |
| Hip fractures: | no reduction |
SAFETY
The most common problems are related to the nasal spray local effects. About one in ten subjects experienced nasal irritation and nasal symptoms, such as crusting. To minimize the delivery effects, you should alternate the spray from nostril to nostril.
Nausea and mild abdominal discomfort with bloating or fullness may occur with the shot form of Miacalcin. These side effects may occur when you first start treatment, but they usually disappear with time. They may be minimized if Miacalcin is taken at bedtime.
EASE OF USE
Administering the nasal spray requires one spray once a day. Remember to alternate nostrils each day. Miacalcin shots are prescribed infrequently and require that you either learn how to give the shot to yourself or have someone else give you the daily shot under the skin.
WHAT SHOULD I EXPECT?
Expect to see very little variation in your bone density, since calcitonin has a minimal effect. It may take longer than two years to see a positive response (improvement or no change in BMD), if any. In the pivotal fracture trial, after two years of treatment with Miacalcin, the average bone mineral density changes were:
| Lumbar spine: | 1% |
| Total hip: | no change |
| Femoral neck: (neck region of hip) |
no change |
FINAL NOTES
If you have suffered a painful spine fracture, Miacalcin may be tried for pain control. This use is “off label.” You will find a description in the section titled “Off Label Uses: What Else Is Being Treated?” (see page 242).
Since salmon is the source of Miacalcin, a potential exists for development of antibodies over time. Fortical was developed to provide a human calcitonin source as an option.
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The Bare Bones
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Forteo:
A Different Approach
Forteo brings to mind the children's nursery rhyme “Humpty Dumpty.” Forteo (teriparatide) does something none of the other medicines can do: It puts back together connections that have broken. You can put Humpty Dumpty back together again with Forteo.
Forteo is an anabolic or bone formation agent. It is the only medicine that targets osteoblasts, the bone building cells. In contrast, all the other osteoporosis medicines' actions are directed at the osteoclasts, the bone breakdown cells.
SCIENTIFIC RATIONALE
Forteo is the first portion of the parathyroid hormone. Your own parathyroid hormone is produced by four small parathyroid glands that sit just behind the thyroid gland in your neck. Its sole purpose is control of your body's calcium. If you do not get enough calcium in what you eat or from a supplement, your parathyroid glands receive a warning signal: calcium levels low. They produce more parathyroid hormone, which causes calcium to be released from the bone, and over time this produces bone loss.
If too much parathyroid hormone causes bone loss, how does giving more parathyroid hormone in the form of Forteo help build bone? A high constant level of parathyroid hormone is what causes problems. Forteo produces a short burst of parathyroid hormone. The extra parathyroid hormone in the short burst generates bone formation by turning on osteoblasts independent of the bone remodeling cycle. It reverses remodeling imbalance and the resorption pits are overfilled in response. The osteoblasts increase in number from precursor cells, work harder, and live longer. In addition, Forteo speeds up the bone remodeling cycle. New bone is formed, connections are reestablished, and bone volume is increased by these actions.
Forteo
(teriparatide)
Category
Anabolic: bone formation
Biologic hormone
Manufacturer
Eli Lilly and Company
Pivotal Fracture Trial
Fracture Prevention Trial
Fracture Reduction
Spine
Nonspine
Indications for Osteoporosis
Treatment for postmenopausal women at high risk for fracture
Men
Steroid-induced treatment
Contraindications
Children and young adults
History of radiation therapy involving the skeleton
Cancer in bone
Other bone diseases
High blood calcium
Other Considerations
History of kidney stones
Possible Side Effects
Pain
Joint aches
Nausea
Leg cramps
Increase in blood calcium
Dose
Pen prefilled with 28 daily doses of 20 micrograms
Automatic injection under the skin once a day; rotate sites on thigh or abdomen
Keep pen refrigerated
Additional Information
Black box warning risk of osteosarcoma in rats
Voluntary patient registry
Maximum lifetime use 2 years
Follow with other therapy to maintain gains
EFFECTIVENESS
Fracture Prevention Trial
The pivotal fracture trial enrolled over 1,600 postmenopausal women with spine fractures and lasted about twenty months. The women were at high risk for spine fractures, and almost two-thirds of the women had two or more spine fractures at entry. Two doses of Forteo, 20 and 40 micrograms, were tested in comparison with a placebo. Forteo was given as a once-a-day shot.
Few hip fractures occurred during this short study time. With less than two years of treatment with Forteo, fracture reduction was robust at the spine and nonspine:
| Spine fractures by x-ray: | 65% |
| Nonspine fractures: | 53% |
| Hip fractures: | too few fractures |
SAFETY
The Fracture Prevention Trial was planned as a three-year study. However, during the second year of the study, laboratory rats developed tumors of the bone called osteosarcoma. These animals received higher doses than those used in the fracture trial. However, the clinical trial was stopped to investigate the appearance of the bone tumor in the rats. After several years, Forteo was FDA-approved with a “black box warning” in the printed package insert about the occurrence of osteosarcoma in rats at higher doses.
Forteo is contraindicated in situations that would put someone at higher risk for development of osteosarcoma. Therefore, Forteo is not given to children or young adults who have not completed their growth. It should not be used by anyone with cancer in the bone, other bone diseases, or history of radiation therapy involving the skeleton. The radiation history excludes women who have had radiation treatment after breast surgery and men with prostate cancer who have received radiation or have cancer that has spread to their bones.
The median time of studying drug use in the Fracture Prevention Trial was nineteen months. The longest duration of medicine exposure was up to two years. Therefore, the use of Forteo is limited to twenty-four months total for your entire lifetime.
The most common adverse events are leg cramps, which usually go away with continued use. First doses may cause decrease in blood pressure, so you may want to take your dose at bedtime to start.
EASE OF USE
Forteo is a shot that you learn to give to give to yourself every day for twenty-four months. The idea of a shot is a big barrier for many who are considering this medicine but it shouldn't be. It is easy to learn how to administer the shot and the time is limited to two years, so you won't have to give yourself shots forever. Forteo is supplied in a pen syringe that holds enough medicine for twenty-eight days of use. The injection is “automatic,” like pushing the top of a ballpoint pen. The needles are tiny, which makes the shots almost painless. A new needle is attached each day and you rotate sites of injection on your lower abdomen and upper legs. The syringe needs to be refrigerated. Do not leave it out after you use it. After disposing of the used needle in a “sharps” container, return the syringe to the refrigerator right away.
A handy tip is to write the end date on the syringe with a permanent maker. That way you will have your last day of use for the syringe. You will not have to keep track and count the number of days along the way.
If you go on a short vacation or trip, you may skip packing your Forteo because of the refrigeration logistics. Resume daily use on your return. For long trips, a travel pouch is included in your starter kit. Your doctor may need to write a letter for the TSA airport security explaining that you must carry needles on board in your hand baggage.
You should plan on taking the first couple of doses at bedtime because of the potential of having lower blood pressure upon standing. After the first week, take the medicine when it is convenient for you.
WHAT SHOULD I EXPECT?
You will be rechecking your bone density after you finish your two years of use. Your bone density changes may depend on whether you used another medicine before Forteo. The specific medicine you used prior to taking Forteo may make a difference, too.
In the pivotal fracture trial with Forteo, which was shorter than two years, the average bone mineral density increases after a median treatment of nineteen months were:
| Lumbar spine: | 9.7% |
| Total hip: | 2.6% |
| Femoral neck (neck region of hip) |
2.8% |
Forteo increases bone density and bone size. Therefore, your repeat DXA may underestimate your actual gains. The density does not give you a measure of the microstructure changes that occurred while you were taking Forteo.
THE EFFECT OF FORTEO ON MICROSTRUCTURE
The bone formation effect of Forteo is shown in these images from bone biopsies of the iliac crest (pelvic bone) taken before and after a course of Forteo. This patient was a sixty-two-year-old woman with osteoporosis who enrolled in the Fracture Prevention Trial (Neer et al NEJM 2002). She received Forteo 20 microgams per day for twenty-two months. Her DXA lumbar spine BMD increased by 10.4 percent and her femoral neck BMD increased by 1.4 percent.
These improvements in bone microstructure and increases in bone size are only seen with Forteo. Its different mechanism of action stimulates the bone-forming cells, osteoblasts, to cause these dramatic changes.
SOURCE: © 2010. Eli Lilly and Company. All rights reserved. Used with permission.
FINAL NOTES
Forteo is intended for postmenopausal women with a high risk for fracture. The lumbar spine response is robust and builds bone. If your spine bone density is low or you have already had spine fractures, this medicine is a good choice to reduce your risk of spine fractures.
The biggest dilemma with Forteo is what to take when you have reached the two-year limit of your course of treatment. When Forteo is stopped after two years of use, bone density rapidly decreases. Therefore, you will need to select another osteoporosis medicine to maintain the gains you made while using Forteo. Before your prescription runs out, make plans with your doctor to make the next choice in your treatment plan.
Forteo is also approved for the treatment of steroid-induced osteoporosis. Although this trial lasted for three years, all uses of Forteo are approved by the FDA for two years only.
As part of the FDA's safety program, a monitoring system is in place for surveillance of osteosarcoma. So far, almost ten years after approval, no excess risk of osteosarcoma has emerged.
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The Bare Bones
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Prolia: In a Class of Its Own
Watching the Academy Awards, you can feel the excitement mixed with tension build until the moment the envelope is unsealed and the results are revealed. The same palpable atmosphere was the experience of waiting for the Prolia (denosumab) results to be presented at an international bone research meeting in 2008. We were all atwitter with speculation about the findings of this novel drug's pivotal fracture trial.
The medicine was the result of an exciting discovery in bone biology made in 1995 when scientists first learned how the bone cells talked to one another. The bone cycle is a well-choreographed dance of the osteoclasts and osteoblasts working together. It was not clear what the cells used for signals to communicate with one another. Researchers found that the osteoblasts were the conductors of the dance. The osteoblasts sent signals to the osteoclasts via messengers. Prolia latches on to the messengers, so they cannot deliver their message.
SCIENTIFIC RATIONALE
Prolia is targeted at the osteoclasts. Therefore, it is an antiresorptive, which is the same category as bisphosphonates. However, Prolia is in a class of its own; it is designated a “monoclonal antibody.” Prolia is a molecule that binds to the messenger between osteoblasts and osteoclasts.
The messenger's job is to kick-start the development of osteoclasts and tell them that it's time to work. Prolia treatment reduces the number of osteoclasts that are made, function, or survive. You can think of Prolia as birth control for osteoclasts. The shorthand scientific name for this action is called RANKL inhibition; RANKL is the messenger that communicates between the osteoblasts and the osteoclasts.
Prolia is potent and decreases bone turnover markers by about 80 percent within days. Since Prolia does not bind to the bone, it does not linger in the body once treatment is stopped. This is an advantage if you are worried about a medicine staying in your bones. But the downside is that you will start losing bone, and stopping Prolia may even cause bone loss more quickly.
Prolia
(denosumab)
Category
Antiresorptive
Biologic monoclonal antibody
RANKL inhibitor
Manufacturer
Amgen
Pivotal Fracture Trial
FREEDOM
Fracture Reduction
Spine
Nonspine
Hip
Indications for Osteoporosis
Treatment for postmenopausal women at high risk for fracture
Contraindications
Low blood calcium
Other Considerations
Caution if immune system is weakened by medicines or illnesses
Decrease in bone turnover
Possible Side Effects
Serious infections
Skin reactions and infections
Pain in back, muscles, arms, and legs
Bladder infection
Nonhealing sore in mouth or jaw
Doses
Shot administered in your doctor's office
Prefilled 60 mg dose given under the skin once every six months
Additional Information
Voluntary patient support program
Stopping leads to increase in bone turnover and bone loss
EFFECTIVENESS
FREEDOM: Fracture Reduction Evaluation of Denosumab in Osteoporosis Every Six Months
The pivotal fracture trial enrolled 7,800 postmenopausal women in a three-year trial. In contrast to other trials, subjects in this study ranged in age from sixty to ninety years old. However, fewer women had spine fractures at the beginning of the study. Approximately one-quarter of subjects were enrolled based on having a spine fracture and low bone density, while the others had bone density in the osteoporosis range.
Subjects received a shot of Prolia or placebo solution under the skin once every six months for three years. A total of six shots were given to each study participant over the course of the study.
After three years, Prolia reduced fracture at all sites:
| Spine fractures by x-ray | 68% |
| Painful spine fractures | 69% |
| Nonspine fractures | 20% |
| Hip fractures | 41% |
SAFETY
The reporting of side effects for Prolia is confusing because the FDA made a change to highlight problems even though the drug may not cause them. The top five adverse events reported were back pain, pain in arms or legs, muscle pain, high cholesterol, and bladder infections. These were the most common in the Prolia group and in the placebo group. Numbers were similar in both groups, but they were a little bit higher in the Prolia group. For example, back pain in the Prolia group was 34.7 percent versus 34.6 percent in the placebo group.
However, more subjects who received Prolia had skin problems, like eczema and skin infections. Serious infections were more frequent with Prolia (4.1 percent) versus placebo (3.4 percent). Other possible side effects include low levels of calcium in your blood and jaw problems called osteonecrosis of the jaw.
The extension of FREEDOM and the other clinical trials will provide longer-term safety data. In addition, a voluntary patient program is in place to capture additional safety information.
EASE OF USE
How you take Prolia is different. You make a visit to your doctor's office to have the shot given to you twice a year—every six months. The shot is given under the skin with a small needle in the upper arm, abdomen, or thigh. Local reactions at the shot site are uncommon. You do not need to do anything special beforehand or afterward.
A program sponsored by Amgen called Prolia Plus is available to you. It helps with reminders for when your next shot of Prolia is due and it will also provide periodic educational materials.
What If You Miss a Dose?
Make arrangements with your doctor's office to get your shot as soon as possible. The effects on the bone-breakdown cells disappear quickly. You do not want a long gap after the six-month interval when your repeat shot is due.
WHAT SHOULD I EXPECT?
In the pivotal fracture trial, after two years of treatment with Prolia, the average bone mineral density increases were:
| Lumbar spine: | 8% |
| Total hip: | 4% |
| Femoral neck: (neck region of hip) |
3% |
Changes observed on your first follow-up DXA at two years may differ; improvement in BMD or no change are both considered positive response to therapy.
FINAL NOTES
In 2007, the FDA initiated a safety program for all new medicine approvals. For Prolia, a voluntary program has been set up for physicians to participate in with their patients. Prior to receiving each dose of the medicine, your doctor will ask you questions about possible side effects.
Prolia is intended for postmenopausal women with high risk for fracture. It may be an option if you did not tolerate osteoporosis medicines in pill form or if you did not achieve positive results with other medicines. Those with reduced kidney function can also take this medicine safely.
Other clinical trials with Prolia are in progress or have already been completed. These research studies are investigating the use of denosumab for other individuals who are at high risk for fracture and for patients with different cancers who are at risk for their cancer spreading to the bone (metastases). A higher dose of denosumab, branded as Xgeva®, is FDA-approved for the prevention of skeletal-related events in patients with bone metastases from solid tumors, such as breast or prostate cancer.
You may be at risk for bone loss after stopping Prolia, similar to what happens with discontinuing estrogen. Before stopping this medicine, discuss with your doctor options to ensure that you maintain your gains.
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The Bare Bones
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Combination Therapy:
Are Two Really Better Than One?
Does it make sense to use two medicines instead of just one? Using two medicines runs the risk of more side effects. The cost of two medicines needs to be factored in as well. A combination of two medicines that work by different mechanisms may make sense. Therefore, different combinations of medicines have been evaluated by measuring bone density and monitoring safety in clinical trials.
ANTIRESORPTIVE COMBINATIONS (TWO MEDICATIONS THAT DECREASE BONE BREAKDOWN)
Bisphosphonates Plus Estrogen
Fosamax plus estrogen, tested in the form of Premarin 0.625 mg, resulted in higher bone density than either medicine alone. At the end of two years, the combination increased bone density at the spine by more than two percent over and above the changes seen with Fosamax or estrogen alone. If you are already taking estrogen and add Fosamax, you can expect a small boost in your bone density, too. Actonel used in combination with estrogen in early postmenopausal women and added to an ongoing estrogen therapy regimen increased bone density more than a single drug. Combining estrogen with other bisphosphonates may also yield increased bone density benefit, but studies have not been done.
Bisphosphonates Plus Evista
The combination of Evista plus a bisphosphonate makes sense. If you are taking Evista for reducing your risk of breast cancer but you have a high risk of hip fracture, Evista may not be enough to reduce your fracture risk. Adding a bisphosphonate may be beneficial, although fracture risk has not been assessed. This combination increases bone density like a “light estrogen.”
YOUR STORIES…
Janice, age sixty-two, checked her bone density after her eighty-six-year-old mother fell and broke her hip. Janice had T-scores of -3.2 at the spine and -2.8 at the hip. When her sister was diagnosed with breast cancer three years earlier, Janice started taking Evista, so she never thought she was at risk for osteoporosis.
After her DXA scan did show osteoporosis, her doctor ordered blood work, and she collected her urine for twenty-four hours. Her vitamin D level, at 18 ng/ml, was below the recommended minimum level of 30 ng/ml. Everything else was in the normal range.
What to do? Evista is still indicated for lowering her breast cancer risk, but it may not be enough to lower her risk of fracture. She and her doctor decided that the next step was to add a bisphosphonate, and generic alendronate was the preferred choice by her health plan.
However, she decided to wait and repeat a bone density in a year to see whether she continued to lose ground while taking Evista. In addition, she wanted time to “clean up” her habits, start back on an exercise program, pay attention to her daily calcium intake, and increase her vitamin D.
ONE ANTIRESORPTIVE AGENT PLUS BONE BUILDER, FORTEO
The effects on bone density have been studied when Forteo and some of the other medicines are given in combination either both at the same time or sequentially—one after the other. However, bone density measured by DXA does not tell the whole story. The three-dimensional microstructure changes expected with Forteo are not captured with two-dimensional DXA scans. They also may underestimate change because bone size increases with Forteo.
Combination results may depend on the bisphosphonate. Taking Forteo and bisphosphonates at the same time produces different responses depending on which bisphosphonate is being used. Fosamax blunts the response and appears to inhibit the bone-forming effects of Forteo therapy. Actonel combined with Forteo did not blunt Forteo's effect; however, it did not show an added effect either.
A study done with Reclast and Forteo suggests that bone density increases faster when these two medicines are combined than when either medicine is used alone. Although spine bone density was similar for combination versus Forteo alone, hip bone density was better with the combination.
For now, a combination of Forteo and a bisphosphonate is not recommended, and in the case of Fosamax, it is not helpful.
These observations may explain the responses when Forteo follows treatment with Fosamax or Actonel, which is common practice. Forteo therapy after Fosamax may show a smaller improvement in bone density rather than a robust increase at the spine. Forteo therapy after Actonel shows the expected bone density increases. Previous use of Actonel does not appear to decrease the response to Forteo.
Bisphosphonates given after Forteo therapy are beneficial. Immediate use of bisphosphonates after completing a twenty-four-month course of Forteo is needed to maintain the increases in bone density. If no treatment follows Forteo therapy, bone density gains are lost.
The dilemma for you may be choosing which medicine to take. Some of you may have switched to Forteo because of difficulty with a bisphosphonate or concern that it was not working.
Combination with estrogens or Evista does not appear to interfere with response to Forteo therapy. If you are already taking estrogen or Evista, you can add Forteo and expect a good response.
Forteo in Combination with Other Osteoporosis Medicines
The bone density response using Forteo at the same time as another osteoporosis drug varies depending on the individual medicine. The majority of combinations do not add to the benefit of Forteo used alone and, in the case of Fosamax, there is actually decreased response. Therefore, combining Forteo with bisphosphonates is not recommended at this time. The new data for Reclast suggest that combination with Forteo may yield benefit, and this combination may be an option for someone with a high risk of spine and hip fractures.
| Forteo Plus… | Bone Density Response Fosamax |
| Fosamax (generic alendronate) |
Decreased |
| Actonel | No added benefit |
| Boniva | No data |
| Reclast | Faster increases Added benefit at hip |
| Estrogen | No added benefit |
| Evista | No added benefit |
Reassess the Reason for Medicines
Before adding any medicine, make sure that you should still be taking your original medicine. Estrogens or Evista along with another osteoporosis medicine are the combinations that may be helpful if there are other indications for their use. Keep in mind that estrogens are recommended for short-term use. If you have been on estrogen for longer than five years, discuss its continued use with your doctor. In the case of Forteo, combination therapy does not necessarily mean added benefit and is not recommended at this time.
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The Bare Bones
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Making a Choice:
How Do the Medicines Compare?
Everyone always wants to know how the medicines stack up against one another. The only accurate way to answer the question is to include all of the osteoporosis medicines in one gigantic study. The medicines would need to be evaluated in a “head-to-head” comparison focused on fractures in similar study participants. Any fracture comparison study would require more than sixty thousand subjects. It is unlikely that such a study will be done. At the present time, there are only several small studies that compare bone density changes using two different medicines at a time.
Hopefully you have come to this point reassured that your risk is high enough for you to benefit from prescription medicine. It is time to figure out “which medicine is right for me.” Take your time to weigh the options. Starting treatment is not an emergency. Do not go into panic mode. You have time to make your decision—unless you are on high-dose steroids that cause rapid bone loss or you have had a recent fracture. During your education and investigation phase, the first step is to optimize your nutrition, exercise, and calcium and vitamin D.
Do not do everything at once. Take a graduated approach; go slow and add one thing at a time. In this way, if an issue arises, like a side effect, you will be able to pinpoint the most likely cause. Is your stomach upset from the new pill or from the calcium supplement? If you need calcium supplementation of your diet, make sure you are tolerating the calcium supplements first before adding an osteoporosis medicine. If your vitamin D is low, take the next two to three months to bring your levels up above 30 ng/ml. Some research suggests that you may be less likely to have muscle pains with bisphosphonates if your vitamin D levels are within normal range. Research in animals showed that jawbone problems are more likely with low vitamin D levels. Take your time.
Prevention and treatment involve many aspects. Minimize your risks by changing whatever is in your control. A prescription is an important part of therapy, but it's certainly not the only part. For example, the majority of serious injuries and fractures are a result of falls. Fall prevention is key. Work on improving your balance and muscle strength.
Compare and contrast to individualize your choices. The task for you and your doctor is to compare your potential choices by looking at the individual medicines and their clinical trial results. Effectiveness in reduction of fractures is of prime importance. Review the summary of the medicines' effectiveness in reducing the risk of fractures. Your history and individual situation will provide a guide for your best options. Your preferences for pills versus other forms of delivery, your history of an ulcer or blood clots, a family history of breast cancer, whether your spine bone density is lower than your hip bone density or vice versa; these are all types of considerations that will factor into your decision.
Reality check: What does your healthcare plan cover? You may want to use a particular medicine but find that your insurance does not cover it or that you have to start with another medicine first. Find out what your healthcare plan covers as its first tier. Most likely it will be generic alendronate, since it is the lowest in price. I did not include the costs of medicines, which are a big consideration, because the “retail” costs are not what you pay out of pocket. Your costs are dependent on your insurance coverage, reimbursement, and co-pays and thus would be impossible to predict. All pharmaceutical companies offer patient assistance programs that may be available to you depending on your financial circumstances. If you are having trouble affording your medicine, talk with your doctor about options.
YOUR STORIES…
Wendy, age sixty-seven, stopped estrogen after twenty years of use because of Women's Health Initiative (WHI) findings and her doctor's recommendations. She has no family history of osteoporosis or any medical problems. She is fit, works out, watches her diet, and doesn't smoke or drink. About two and a half years after stopping estrogen, she had an accident in her home. Her foot got tangled in a footstool, which caused her to fall. She caught herself with her right hand outstretched, breaking her right wrist and left foot. Her baseline bone density was measured at age sixty-five, about the time she stopped taking estrogen. Her follow-up bone density was done just after her fractures. She had lost bone density at both her spine and hip in the two and half year interval. This loss in bone density is shown as percent change in the last column of the following table.
The bone density shows a significant decline at her hip and spine. This rapid loss is similar to early menopause with the loss of estrogen. Because she had stopped estrogen therapy, Wendy had both accelerated bone loss and an increased risk of fracture.
Her evaluation included a search for other causes of bone loss. No related problems were uncovered; her healthy lifestyle did not need any major modifications. She decided, in consultation with her doctor, to begin taking medicine to stop her bone loss. Her health plan covered alendronate (generic Fosamax), which she started once a week without any difficulty.
FDA-Approved Medicines for Treatment of
Postmenopausal Osteoporosis: Comparison of
Fracture Reduction
The goal of therapy is reducing your risk of breaking a bone. These medicines increase bone density, and even modest improvements translate into reduction of fractures. However, the sites of fracture reduction are not uniform. The following table summarizes the types of fracture that were reduced in the pivotal fracture trials of each medicine.
Generic alendronate is not listed because the fracture trial used brand Fosamax. Generic alendronates had similar characteristics in short-term evaluations that showed the body handles the generic compound in the same manner as the brand.
You should note that estrogen is approved only for prevention of osteoporosis, although a reduction in fractures at all sites is observed with its use. For Boniva, only a subset of women who had T-scores of -3.0 or lower at the neck region of the hip showed fracture reduction at nonspine locations. Forteo is the only bone-formation medicine on the list. Its use is limited to a maximum of twenty-four months and should be followed with another osteoporosis medicine to maintain benefit. Calcitonin nasal sprays, Miacalcin or Fortical, increase spine bone mineral density but have uncertain fracture efficacy.
Thinking about your choices. The above summary of fracture efficacy is a guide for starting your process of selection and discussion with your doctor. Since the goal is preventing fractures, the top choices are medicines that decrease risk of fractures at all sites. For treatment of postmenopausal osteoporosis, Fosamax and Actonel are the top medicines in pill form that have effectiveness at all sites. Now that Actonel is available for once-a-month dosing or in the form of Atelvia, which can be taken after breakfast once weekly, it rivals Boniva's ease of use with better efficacy. Reclast is potent and long lasting and is given by vein. It is a choice if you are unable to take a pill or if you want to take medicine only once a year.
Given as an injection twice a year, Prolia is an alternative to oral medicines. It has quick on and off action and is not incorporated in the bone. Some people are choosing Prolia because they are fearful of bisphosphonates that stay in the bone. However, because of its potency, Prolia has the potential for similar side effects as bisphosphonates. You should consider Prolia if you are at high risk, have not had adequate results from other medicines, or are unable to take other osteoporosis medicines. Prolia is also an option for those who have reduced kidney function.
Forteo is a short-term choice for high-risk individuals that offers a way to build bone microstructure, particularly in the spine. If you have already sustained fractures in your spine or have low spine bone density with a high risk for fractures, Forteo is an excellent option. After completion of a two-year course of Forteo therapy, you need to follow up with one of the other osteoporosis medicines.
Evista may move up to your first choice if you have a family history of breast cancer. If you are at high risk of fracture, you may consider combining Evista with another medicine, since you do not get fracture reduction beyond the spine. Caution: If you are early postmenopausal with hot flashes and sweats, these may increase with Evista. You may want to delay using it until your menopausal symptoms improve, and choose something else in the interim.
Boniva is a second-tier option because fracture reduction was observed at the spine only. However, if you have a T-score at the neck region of the hip of -3.0 or lower, it could be a top-tier option, since this subgroup of women subjects had fracture at nonspine sites.
Calcitonin used to be reserved for individuals who could not take or tolerate medicines by mouth. Now that effective choices are available by injection or infusion, calcitonin has lost its role as the only nonpill option. With its lack of efficacy, calcitonin should no longer be part of the medicine chest for treatment of osteoporosis.
YOUR STORIES…
Julie, age sixty, had a difficult transition through menopause. It was not so much hot flashes and night sweats, but all the other changes in her life. When her last child left for college, she thought she would be rejoicing, but instead she became depressed. Eventually, she was started on an antidepressant, Lexapro; she also saw a therapist.
At her doctor's suggestion, she had a DXA scan. She was surprised that she was diagnosed with osteoporosis. Her bone density results showed a T-score of -2.8 at the lumbar spine and she was within the normal range at the hip. She discussed possible treatment options with her doctor and decided on the convenience of once-a-month Actonel.
YOUR STORIES.
Donna, age fifty-five, had a bone density done because of her family history of osteoporosis. Her mother had fractured her hip at age eighty-seven. Her mother also had had breast cancer in her early sixties.
Her bone density results T-scores were -1.1 at the lumbar spine, -0.7 at the total hip, and -0.6 at the neck region of the hip (femoral neck). Her calculated ten-year probability of a major osteoporotic fracture was 5.6 percent and for hip fracture it was 0.3 percent.
Her fracture risk was low. However, she was one year past menopause, so a higher rate of bone loss would be expected over the next several years. In order to protect her bone mass and decrease her risk of breast cancer, Evista was prescribed. It did not increase her hot flashes.
Other Considerations
A few situations warrant special attention in making your selection. History of some problems eliminates choices or makes others more advantageous.
YOUR STORIES…
George, age sixty-eight, had been struggling with worsening of his emphysema. He had been on and off prednisone to control his recurrent flare-ups but now was taking prednisone 10 mg every day. It seemed that when he went to a lower dose his breathing got worse, which necessitated the use of oxygen at night. One night, he became entangled in his oxygen tubing, which caused him to fall. He hit his dresser on his way down and the blow to his chest caused severe pain and worsening of his breathing. He had his wife take him to the emergency room where he was diagnosed with a rib fracture and a spine fracture. The emergency room doctor told him he had osteoporosis.
George followed up with his primary care doctor, who referred him to a rheumatologist specializing in osteoporosis. George was told that he had severe osteoporosis and was at high risk for more fractures. He was prescribed Forteo to decrease his risk of another fracture and to counteract the bone loss from prednisone. Calcium and vitamin D were also added to his regimen. He was sent to physical therapy and pulmonary rehabilitation to reduce his risk of falling.
REVIEW EACH YEAR
Keep in mind that whichever medicine you choose to start with may not be the medicine you continue using “forever.” A decision to start one medicine today does not commit you to taking that drug for the rest of your life. Each year, you and your doctor should re-evaluate your treatment options. It should include a review of your lifestyle habits and the medicines you're taking, not just for osteoporosis but for everything, including over-the-counter medicines, vitamins, and supplements.
You may want to consider some of these questions when talking with your doctor:
- Are you tolerating your medicine?
- Is it fitting easily into your lifestyle?
- Is the medicine working?
- Is there new information about the medicine you are using?
- Are there new options available that may be better?
- Are you doing “all the right things” in your lifestyle?
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The Bare Bones In choosing which medicine is right for you:
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Off-Label Uses:
What Else is Being Treated?
Each medicine approved by the FDA has indications for its use spelled out clearly in the product information or “label.” From clinical-trial observations or after widespread prescription use of a medicine, other beneficial effects may be observed. In some cases, further investigation has been done or information has become available from current but incomplete clinical trials. This leads to doctors prescribing the medicine in a non-FDA approved, or “off-label” capacity. Pharmaceutical companies are very, very careful not to mention any off-label uses. Big fines have been levied on those who have made that mistake. The most common off-label uses of osteoporosis medicines are for helping in pain relief and for fracture healing.
CALCITONIN:
ACUTE PAIN FROM SPINE FRACTURE
One use for calcitonin that may be worth trying is for relief of acute pain associated with a new spine fracture. Spine fracture with pain can be incapacitating. Use of calcitonin is one way to try to minimize the use of narcotic painkillers.
If you or your family member is older, you can talk with the doctor about using daily calcitonin for a short time. In studies, the use of narcotics decreases usually within three to four days. If calcitonin works, you will know usually within the first week. Response to calcitonin may be as high as 80 percent. It will not work for everyone, but it may be worth trying.
If you or your loved one needs some extra assistance during this time, talk with the doctor about ordering calcitonin as a daily injection for the acute pain. In this way, getting a home health nurse to make daily visits may be a possibility.
If the idea of a shot does not interest you or you do not need home health support, use the nasal spray. A double dose of nasal spray, two sprays a day, equivalent to a daily shot of 100 IU, may help.
Calcitonin is thought to provide pain relief by a direct effect on pain threshold centers in the brain. The analgesic effect of calcitonin is attributed to the increase in circulating endorphins, which are chemicals that can block sensations of pain and act as your body's own pain relievers.
FORTEO: FRACTURE HEALING
Repair of a fracture requires increased transient bone formation at the fracture site. Since Forteo increases bone formation, it may be a potential agent to boost fracture repair. Faster healing of fractures was observed in patients already on Forteo who had recently experienced a fracture and in patients who had switched to Forteo after a fracture.
To date, only one randomized clinical trial of Forteo and fracture healing has been conducted. The study evaluated one hundred postmenopausal women who had experienced wrist fractures that did not require surgery. Subjects were divided into three groups, two of which received doses of Forteo. The two Forteo groups received either the marketed 20 microgram dose or a 40 microgram dose daily for eight weeks. The third group received a placebo daily for eight weeks. The treatment was started within ten days of fracture, and x-rays were taken every two weeks. The study failed to show significant difference in healing time between the 40-microgram and placebo groups. However, the standard-dose group showed a statistically significant acceleration of healing.
The type of fracture may make a difference. Since Forteo has the largest impact on the spine, healing of spine and other bone sites rich in spongy trabecular bone like the pelvis and the ends of long bones may benefit. Some clinicians have reported success with pelvic fractures healing in half the time. In addition, pain associated with the fracture improved faster.
Other reports of success include the healing of fractures that had previously failed to heal and had showed little healing activity on a bone scan or other imaging. Stimulation of bone formation by Forteo led to consolidation of bone, where time, surgery with bone grafting, or revisions had failed. Among those in the orthopedic community, additional interest has developed in using Forteo for healing following fusion operations, especially in patients who are at high risk for poor healing due to other problems like diabetes or hardening of the arteries.
YOUR STORIES.
Rene, age seventy-one, was watering her garden when her telephone rang. She turned quickly, caught her foot on the garden hose, and landed square on her back with her bottom hitting first. She got up and walked into the house but had intense pain in her right groin. She called her daughter-in-law, who drove her to the emergency room.
Diagnosis: pelvic fracture. She was hospitalized. Her fracture did not require surgery but it did require watchful waiting and time to heal. Based on some recent success with other patients who had experienced pelvic fractures, her doctor started her on Forteo. Pain subsided within three weeks and Rene only experienced discomfort on days with longer physical therapy. Six weeks after her fracture, Rene was back out watering her garden, this time with her portable telephone clipped to her belt.
FORTEO: BACK PAIN
Observations made in clinical trials with Forteo and from reports by patients taking Forteo suggest that it may also lessen back pain. A combination of data from several clinical trials showed that Forteo reduced back pain by a third overall and by more than half in those with severe back pain. The analysis also looked at trials with estrogen and bisphosphonates. The risk of back pain was lower in Forteo-treated subjects compared with estrogen- or bisphosphonate-treated subjects. The finding suggests that Forteo may have different effects on back pain than other osteoporosis therapies.
One theory is that Forteo reduces back pain by reducing the occurrence of new spine fractures. How it may modulate pain from other causes is not clear. The two-year limit on treatment means that you cannot use it over the long term, but short-term therapy for reduction of back pain is being investigated in a clinical trial.
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The Bare Bones Caution with these uses: Off-label treatments are not approved by the FDA.
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Hot Topics: Cocktail Party Conversations
After people ask me, “What do you do?” at a cocktail party or get-together, the next question never fails to be about bone health. “What do you think about…” Usually, I am quizzed about the latest related topic to hit the media.
There are no definitive answers to the hot topics. Drug safety and the consequences of long-term use of medicines are topics of debate both in the bone health community and in the media. More research is needed to find the answers. Because medicine is an ever-evolving field, today's knowledge will inevitably be supplanted by future findings. Here is what is known so far about the controversies in treatment of osteoporosis.
SHOULD YOU TAKE A “DRUG HOLIDAY”?
How long should you take osteoporosis medicine? The answer to this question is far from certain and the evidence is thin in this area. Many doctors are now proposing to their patients on bisphosphonates that they should take a drug holiday. What does “drug holiday” mean? If you have been on one or more of the bisphosphonates (Fosamax, Actonel, Atelvia, Boniva, or Reclast) for five or more years, should you consider stopping your medicine for a year or two and then resume your medicine?
Most of the clinical trials have treated subjects for only three or four years. Some trials have continued with extensions to their fracture trials. The longest experience in clinical trials has been the use of Fosamax for ten years. The extension of the Fracture Intervention Trial (FIT), called FLEX, tried to answer the question, “If you increase your bone density, should you continue to stay on medicine?” The FLEX results provide some guidance, but the answer is still not cut-and-dried.
If you have achieved a bone density at the femoral neck of better than -2.5 after five years of treatment and you are not at high risk for fractures, you may consider discontinuing your medicine. If your hip bone density is still low, or you have had a spine fracture or are at high risk for fracture, you should continue taking prescription medicine.
The next question is, “What happens if you stop your medicine?” Bone breakdown and bone loss will occur again. However, the timing depends on the individual medicine.
Once Fosamax has been stopped, bone turnover gradually revs back up within about five years. Actonel has a shorter time frame of two to three years. Data are absent for Boniva and Reclast, but similar effects are expected based on strength of binding to the bone. Boniva would be comparable to Actonel and Reclast would be comparable to Fosamax. An analysis of one dose of Reclast showed fracture-reduction benefit for about three years. More data on Reclast will be available in the near future.
For Fosamax, about 70 mg of medicine is retained in the skeleton after ten years of therapy with 10 mg a day or 70 mg a week. The sustained effect of bisphosphonates may be the result of recycling. In other words, bisphosphonates retained in the bone may be released at new sites of bone remodeling. The recycled bisphosphonate may bind again to bone surfaces. Upon stopping treatment, the release of Fosamax from remodeling is estimated to be approximately the same as taking a daily dose of 2.5 mg. This results in a gradual upward trend in bone turnover rather than a rapid increase.
In contrast, bone turnover resumes right away after stopping other osteoporosis medicines. Bone loss restarts quickly when stopping Evista, estrogens, Forteo, or Prolia because these medicines are not retained in the bone. Ending a course of treatment with estrogens, like the loss of estrogen in natural menopause, results in rapid bone turnover. During this time of rapid loss, you may also be at higher risk for fracture. After therapy with Forteo, additional treatment with another medicine is required to preserve gains. Discontinuation of Prolia results in a rapid rise of bone remodeling, a transient increase in bone turnover markers above the pretreatment level, and an associated rapid decline in bone density.
If you have been on bisphosphonates for five to ten years or more, talk with your doctor about a drug holiday. In general, if your bone density has increased above the osteoporosis threshold this may be an option. A holiday of two to three years for Fosamax and Reclast, and a shorter holiday of one to two years for Actonel or Boniva, may be a consideration. If you are still in the osteoporotic range and at high risk for fracture, you want to remain on the same medicine or use another medicine, not a bisphosphonate, for one to two years before continuing with the bisphosphonate. Although no data supporting the latter recommendation are available at this time, many experts are now suggesting this option.
If you are on medicines other than bisphosphonates, stopping your medicine may lead to rapid bone loss. To protect the gains you made while on therapy, you need to plan ahead before completing two years of Forteo or stopping Evista, estrogens, or Prolia.
If you stop treatment, another important question follows: When do you restart? Here is where bone markers may be helpful in addition to bone density. Checking a bone turnover marker may possibly indicate when the effect of the bisphosphonate is waning. However, be wary: this is a “data-free” zone. At this point, there is no evidence that fracture risk remains reduced when you have discontinued your medicine, even if bone markers are reduced and bone density is stable.
The scant data available to direct decisions relating to duration of treatment and drug holidays has given rise to lively debates and all types of advice. You and your doctor must weigh your risks and benefits in formulating a prudent plan of action.
JAWBONE PROBLEMS
For a while, it seemed that one could not open a newspaper or turn on a television without seeing an advertisement inquiring, “Do you take Fosamax and have jaw problems? Contact our law firm.”
The term for these jawbone problems is “osteonecrosis of the jaw” or “ONJ” for short, which refers to the development of lesions of the jaw that do not heal within eight weeks. ONJ may begin after one has had a tooth pulled or has had an injury to the mouth that exposed the bone. Very rarely, there may be spontaneous occurrence without a dental cause. ONJ may result when a sore at the site of exposed bone worsens. When this happens, part of the bone may become dead tissue characterized by an angry-looking area of yellow or white bone with swelling and drainage of pus.
The first case reports of ONJ in 2003 were in cancer patients receiving intravenous bisphosphonate therapy. They received higher doses than are used for osteoporosis. When the same problem occurred in patients receiving oral bisphosphonate therapy for osteoporosis with no history of cancer or chemotherapy, a possible association was established between ONJ and bisphosphonate therapy.
A review of clinical trials using bisphosphonates showed no reported cases in any of their phases. The extension studies with Actonel and Fosamax for seven and ten years of use uncovered no cases. However, it is common for rare adverse drug effects to be uncovered during postmarketing surveillance.
Multiple groups assembled expert panels to characterize the problem and set up guidelines. In 2006, the FDA issued a broad, class-wide warning for all bisphosphonates, including pills and intravenous preparations.
In 2007, the leading bone researchers in a task force for the American Society for Bone and Mineral Research released their report. The estimated number of cases was one to ten cases of ONJ for every one hundred thousand persons receiving treatment. For cancer patients, the risk was greater at one in ten thousand. Cancer patients have a higher risk, particularly if they are receiving radiation to the mouth region or chemotherapy for head and neck cancer. Also, they may receive higher doses of the bisphosphonates. Regular dental visits are recommended for oral health maintenance.
Risks for Jawbone Problems (ONJ)
- Intravenous bisphosphonate users are at greater risk than those using oral bisphosphonates
- Cancer patients
- Oral surgery or removal of teeth
- Poor dental hygiene, failure to care for teeth
- Periodontal disease
- Poor-fitting dental appliance
- Use of drugs for two years or more
- Smoking
- Alcohol abuse
- Diabetes
- Steroid use
If you are planning on dental surgery, talk with both your dentist and your prescribing doctor. Multiple medical and dental organizations have issued guidelines and recommendations. It is not known if stopping the bisphosphonate will make a difference in lowering the risk of ONJ. One specialty dental organization, the Association of Oral and Maxillofacial Surgeons, recommends stopping your bisphosphonate three months before an elective procedure and waiting until three months after to restart.
You may see this condition referred to as bisphosphonate-induced ONJ. However, any potent medicine that decreases bone turnover has the potential to cause the problem, including Prolia or any bisphosphonate. Label updates for all bisphosphonates include the possibility of ONJ. Prolia's label also specifies a risk of ONJ. Since the bone turnover markers start trending up with Prolia before the next six-month dose, you could wait to have a dental procedure until bone markers increase if it is not an emergency.
What is the cause of ONJ? It is not known. One interesting study out of the UCLA School of Dentistry suggests that vitamin D deficiency may be the cause. The UCLA researchers gave Reclast to laboratory animals. Some animals had vitamin D deficiency and others were supplemented with vitamin D. In their experiment, only the animals with low vitamin D developed jaw problems.
Vitamin D has not been assessed systematically in people who developed ONJ. But it makes sense to be sure that you have an adequate vitamin D level before starting a course of treatment on any bisphosphonate or Prolia. In addition, you should have an oral examination before beginning therapy.
Nevertheless, a robust remodeling system is essential for maintaining bone health. The pressures on the mandible are the highest exerted in the body. The frequency with which the mandible is mechanically loaded may explain why these uncommon adverse events may occur at this skeletal site.
Some have speculated that ONJ is related to oversuppression of bone turnover, which refers to a rate of bone turnover that is so low that the bone can't maintain itself. However, levels of bone turnover markers achieved with therapy do not appear to be correlated with risk of ONJ. Some individuals recommend checking bone turnover markers; if they are low, do not proceed with your dental work. But this is only the opinion of some experts, and it is not proven.
Take care of your dental health with routine checkups and oral exams. Avoid trauma to the tissues in your mouth. Carefully weigh the risks of any elective dental procedure involving bone. If dental treatment is required, such as removal of several teeth, do one at a time.
DOES TREATMENT CAUSE FRACTURES? CASES OF “ATYPICAL FRACTURES”
On March 8, 2010, ABC World News reported that Fosamax causes fractures. Barely a minute went by before my cell phone started ringing. “Dr. Di,” one friend said, “I just watched the evening news and I am in a panic. Should I stop my medicine?”
In the segment ABC World News Investigates, medical correspondent Dr. Richard Besser described fractures spontaneously occurring in the thighbone below the hip in women treated with Fosamax. The story was retold the following morning on Good Morning America. These broadcasts created a flurry of additional media stories on “atypical fractures” and Fosamax.
Cases of atypical femur fracture in women taking the bisphosphonate class of osteoporosis medicines that includes Fosamax (generic alendronate), Boniva, Actonel, and Reclast had been reported at previous bone meetings and in the literature starting in 2005. Why all the attention in March 2010? The March meeting of the American Academy of Orthopedic Surgeons had several presentations on bisphosphonate-associated fractures that caught the attention of reporters who investigated further and created major media stories.
The media buzz ultimately produced positive steps toward characterizing the problem in depth. In mid-October 2010, the FDA issued a safety communication regarding atypical femur fractures and required labeling changes for all bisphosphonates approved to treat osteoporosis (Fosamax, Actonel, Atelvia, Boniva, Reclast, and generic products). Labels for these medications are now required to indicate the possible risk of unusual fractures of the femur. Although atypical femur fractures have been reported in bisphosphonate-treated patients, the cause of atypical femur fractures has not been established and the risk has been estimated to be rare—less than one percent.
What is an atypical femur fracture?
An atypical femur fracture is a fracture that occurs below the hip in the subtrochanteric region or in the shaft area of the thighbone, or femur. These fractures show characteristics that are not typical of osteoporotic fractures. Therefore, they are labeled “atypical femur fractures.” The fracture may start as a stress fracture and progress to a completed fracture with little or no trauma.
The majority of patients who had atypical femur fractures experienced dull, aching pain of the thigh for months or even years prior to the fracture, and about one-quarter had involvement of the opposite femur as well. If you develop thigh or groin pain while taking bisphosphonates, contact your doctor to have your symptoms evaluated. Since changes may occur in both sides even though only one is symptomatic, both upper legs need to be looked at.
The large health plan in California, Kaiser Permanente, is one place to which the FDA went for numbers. Dr. Richard Dell, an orthopedic surgeon who spearheads a healthy bone program, has been systematically looking at fractures in Kaiser's northern and southern California operations. Kaiser treated more than fifteen thousand patients with fractures of the femur over three years (from 2007 to 2009). Of those, 135 were classified as “atypical femur fractures.” About one-quarter had fractures in both femurs. A total of ninety-eight women sustained these fractures. Five individuals had never taken any bisphosphonates. In the others, the average duration of bisphosphonate use was six years. Dr. Dell estimated that more than three hundred thousand Kaiser patients have been treated with bisphosphonates, and that these medicines have helped prevent more than five thousand hip fractures in just three years, a period during which fewer than a hundred patients sustained an atypical fracture.
This topic is being discussed in every forum imaginable. For example, a debate at a large conference of endocrinologists pitted Dr. Joseph Lane, an orthopedic surgeon from New York's Hospital for Special Surgery against Dr. Juliet Compston, a bone scientist at the University of Cambridge. The participants typify the two disparate views. The orthopedic surgeons did not see this unique type of fracture until about 2000—five years after the FDA approved Fosamax. Since orthopedists see the individual patients who have the problem, they think it is not unusual or rare. Dr. Compston, who counts the numbers based on review of the clinical trials and the literature, thinks it is rare.
Clearly, more information is needed. What is known so far is that atypical femur fractures occurring in the thigh below the hip are statistically rare. A systematic accounting of cases is underway. Your chance of having an osteoporotic fracture is far greater than your chance of having an “atypical” one. At this time, it is not known who exactly may be at risk, whether a pre-existing problem is associated with developing this type of fracture, or how their occurrence may be a result of treatment.
ARE MEDICINES CAUSING
“OVERSUPPRESSION”?
Underlying all of these topics is the question: Are antiresorptive medicines causing oversuppression? In other words, has bone remodeling been slowed down so much that it is harmful? You may have seen this problem referred to as “frozen bone.” This means that bone remodeling is no longer occurring at a sufficient rate for the bone to repair itself. It is as though the construction workers have a work stoppage and aren't showing up for work. The building, after a time, falls into disrepair.
Reducing bone remodeling is how the antiresorptives work, and the effect varies from treatment to treatment. The bisphosphonates are more potent than Evista or calcitonin. The potency of the bisphosphonates differs. Fosamax binds to the bone more strongly than Actonel or Boniva. Reclast is potent and has a rapid and protracted effect, which is why it is given only once a year. Prolia has a rapid and greater effect than bisphosphonates on bone turnover, but it is shortlived and reversible.
The clinical trials are constructed carefully to follow safety protocols and to collect as much information as possible. Bone markers are the measure of bone remodeling. Biopsy of the bone is the only way to get a direct examination of the microstructure. All clinical trials collect a small number of biopsies from each study group to examine the effect of the medicines. Normal mineralization and structure must be demonstrated to get FDA approval. The longest clinical experience with Fosamax, at ten years, showed normal bone formation and bone structure. Normal mineralized bone is formed with all the osteoporosis medicines.
Concerns about oversuppression have been raised by case reports of individuals treated with bisphosphonates who fracture and have bone turnover below the normal premenopausal levels. These observations occurred in postmarketing of the medicines but not during clinical trials, which may mean that they are rare, that the duration of the studies was too short, or both. In addition, oversuppression has been discussed but not proven as a possible cause of both ONJ and atypical femur fractures. The mechanisms for these events have not been worked out. Whether there are certain predispositions or genetic characteristics that increase risk is being investigated.
Based on normal biopsies and the fracture reduction seen with treatment, the effect of reduced bone turnover appears to be beneficial rather than harmful. Monitoring will continue to address concerns about bone safety.
OTHER CONCERNS
Bisphosphonate therapy was implicated in an increased risk of irregular heart rhythm called atrial fibrillation. However, continued patient follow-up proved that it was related to heart problems and not to use of osteoporosis medicines. Early on, questions were also asked about the risk of esophageal cancer. In 2010, a systematic evaluation of esophageal cancer showed that risk did not go up with bisphosphonate medicines. After that report was published, a second paper found a small increase in risk with five years' use of bisphosphonates. While it is not unusual to have conflicting evidence, in this case, both reports used the United Kingdom patient population database. Nonetheless, it appears that, overall, esophageal cancer is a rare event.
NO MEDICINE IS 100 PERCENT PERFECT
All medicines have potential side effects. As with any medicine, you must weigh the benefits of treatment against the potential risks. Recommendations have evolved over time. Doctors once advised everyone with low bone density to take medicine to increase bone density; treatment is now focused on only those patients with a higher risk of fracture. If you have had a fracture, have multiple risks with low bone density, or have a bone density score lower than -2.5, the benefits of lowering your risk of fracture definitely outweigh the risks of side effects. Talk with your doctor to make sure treatment is appropriate, and reassess its continued use every year.
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The Bare Bones
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