Given the prevalence of osteoporosis and the rise of bisphosphonate medications, this author offers a thorough review of the literature and key insights from her clinical experience in treating this condition.

An estimated 10 million people in the United States have osteoporosis and another 34 million have low bone mass, placing them at increased risk for osteoporosis. Nearly 80 percent of people with osteoporosis are women. In fact, the lifetime risk for osteoporosis-related fractures among women is 50 percent. In men, the lifetime risk is approximately 15 percent.¹

There are more than 1.5 million osteoporosis-related fractures each year in the United States. These fractures include 700,000 vertebral fractures, 300,000 hip fractures and 250,000 distal forearm fractures. Hip fractures are the most debilitating and have the highest mortality rate. One in five patients with osteoporosis will die within one year of sustaining a hip fracture.^1-4

Despite the increasing awareness of osteoporosis and the availability of effective drugs to reduce fracture risk, osteoporosis is still under-diagnosed and under-treated, even in older adults with a recent history of low trauma (fragility) fracture.

Approved medications indicated for the prevention and/or treatment of postmenopausal osteoporosis in the U.S. include: bisphosphonates, estrogen or hormone therapy, raloxifene (Evista, Eli Lilly), intranasal salmon calcitonin and teriparatide (Forteo, Eli Lilly). There are no head-to-head trials specifically designed to compare the anti-fracture efficacy of the approved osteoporosis therapies.

Currently, three bisphosphonates are approved for the prevention and treatment of osteoporosis in postmenopausal women and two are approved for use in men with osteoporosis. Research has shown that these agents increase bone mass and reduce the risk of fractures at the spine, hip or wrist.^2,5-7

These modalities are antiresorptive medications that slow bone resorption and increase mineralization during the bone remodeling cycle, resulting in a reduction of bone turnover and maintenance or improvement in bone mass.^2,8 The bisphosphonates — alendronate, risedronate and ibandronate — have consistently demonstrated statistically significant efficacy in reducing vertebral fracture risk.^5-7 Alendronate and risedronate are also effective at reducing non-vertebral fracture risk.^5,6 See “A Guide To Indications And Dosing For Bisphosphonates” below.

Other bisphosphonates include etidronate (Didronel, Procter and Gamble), pamidronate (Aredia, Novartis), tiludronate (Skelid, Mayne Pharma) and zoledronic acid (Reclast, Novartis). They all vary chemically from alendronate and risedronate but are in the same drug class. However, none of these drugs are approved for osteoporosis prevention or treatment. Most of them are approved for other conditions.

What The Guidelines Reveal About Initiating Medications
The National Osteoporosis Foundation (NOF) guidelines recommend initiating pharmacologic therapy to reduce fracture risk in women with:
• bone mineral density (BMD) T-scores via central dual energy X-ray absorptiometry (DXA) of less than -2.0 with no other risk factors or less than 1.5 with one or more risk factors; or
• prior vertebral or hip fracture.^1,8

Prior to initiating treatment for osteoporosis, clinicians should rule out secondary causes such as celiac disease and hyperthyroidism. Approximately half of all men with osteoporosis have a secondary cause. Up to 60 percent of patients taking bisphosphonates are deficient in Vitamin D. Up to 52 percent of older adults in the U.S. are vitamin D deficient.^1,9,10

When AntiresorptiveTherapy Fails
Why do some patients fail to respond to antiresorptive therapy? Outside of the given medication’s mechanism of action, other possible reasons for failure include compliance and underlying secondary causes of osteoporosis that may not have been treated.

Unfortunately, less than 20 percent of patients with osteoporosis are properly treated or treated at all.

There are other considerations. The patient’s bone loss may not have resulted from high bone turnover. The therapy may have simply not worked for the patient or too much damage may have already occurred. Antiresorptive therapy reduces osteoclast activity and promotes strength preservation if the connectivity of the trabecular is preserved. However, if too much damage has already occurred to the microarchitecture and the connectivity has been lost, the opportunity to refill cavities is also lost.^8,10

How To Address Patient Compliance Issues
Unless patients take medication as prescribed, they cannot be expected to demonstrate any significant efficacy. Several studies have shown that the national average of compliance is 20 to 35 percent for women taking bisphosphonates.^1-3,8 Whether it is intentional or unintentional, poor compliance can stem from issues with adherence and/or persistence with a medication regimen.

Other possible reasons for a lack of compliance include cost concerns, forgetfulness, other priorities, side effects or a concern over side effects, a preference for a different medication, a lack of belief in the medication’s effectiveness, a lack of information and a decision to stop taking the medication.

There are steps clinicians can take to help improve compliance. Work with the patient. Taking a medication every other week may be better than nothing. Take the time to listen to the patient and address any fears he or she may have over potential side effects. Emphasize the value of treatment. Give clear, simple instructions and provide written instructions as well. Provide medication reminders on the day of medication administration.

It is also important that patients start or continue taking calcium and vitamin D supplements in addition to treatment. Current guidelines recommend at least 1,200 mg daily for men and 1,500 mg daily for postmenopausal women. Patients should take calcium supplements twice a day. When patients are taking weekly or monthly bisphosphonates, suggest that they omit the first calcium dose on the day they take their bisphosphonate medication. This may serve as a reminder to take the bisphosphonate and prevent poor bisphosphonate absorption that may occur if patients take the calcium supplement too closely to the bisphosphonate dose.^1-3,8

Instruct your patient to take any oral bisphosphonate first thing in the morning on a completely empty stomach with six to eight ounces of plain tap water. He or she should stay upright, sitting, standing or walking for 30 minutes with alendronate and risedronate, and 60 minutes with ibandronate.

A Guide To Indications And Dosing For Bisphosphonates

Your patient should refrain from actions in which he or she reclines or bends forward (gardening, vacuuming, etc.) in order to prevent the possibility of reflux. Explain to your patient that the stomach absorbs this type of medication slowly. Avoiding such actions prevents reflux into the esophagus that may lead to esophagitis. Advise patients not to take their medication if they are experiencing any gastrointestinal difficulties not related to the medication such as reflux, dyspepsia, nausea, vomiting or abdominal pain. If symptoms completely resolve, patients can resume their medication the following week. Otherwise, instruct these patients to inform their health care provider.^5-8

Clearing Up Misconceptions About Osteonecrosis Of The Jaw
All bisphosphonates have similar side effects including gastrointestinal problems such as reflux, dyspepsia, nausea and abdominal pain. Other possible adverse events include difficulty swallowing, esophagitis, esophageal erosions, esophageal ulcers and rarely, esophageal stricture and perforation. Gastric or duodenal ulcers have also been reported. There have been infrequent reports of severe and occasionally incapacitating bone, joint and/or muscle pain. Hypersensitivity reactions have included urticaria and, rarely, angioedema. Additionally, research has reported rare occurrences of visual disturbances and osteonecrosis of the jaw (ONJ) with bisphosphonates.^1,5-7

Osteonecrosis of the jaw occurs when bone in the lower jaw or, less commonly, the upper jaw becomes exposed. This typically occurs after dental extraction or other trauma to the jaw when a resulting wound fails to heal in the usual timeframe.
This condition has occurred in a small percentage of patients with cancer recieving intravenous therapy and rarely in patients with benign conditions such as osteoporosis who are treated with oral bisphosphonates. Of the reported cases, nearly 95 percent were cancer patients who received intravenous bisphosphonates such as pamidronate (Aredia, Novartis) or zoledronate (Zometa, Novartis).¹⁰

Although cases of ONJ are rare, they have been linked to the use of oral bisphosphonates. This prompted the Food And Drug Administration (FDA) to require a statement in the safety information provided in the package inserts for all bisphosphonate products. To increase safety with oral bisphosphonate use, clinicians should ensure their patients understand the benefits and potential risks and side effects associated with these medications. Emphasize regular dental checkups and remind patients to inform their dentist of all medications they are currently taking.¹⁰

The NOF believes the benefits of bisphosphonates outweigh the potential risk of ONJ in the majority of patients. However, if a patient has to undergo dental surgery that involves bone, one may consider a “drug holiday” from bisphosphonate use shortly before dental surgery and not resume until there is local healing. Additionaly, there is no clinical evidence that suggests this will affect the incidence or severity of ONJ.^2,8,10,11

Final Notes
More than 10 million Americans have osteoporosis, resulting in 1.5 million fractures per year. Although there is no cure, our treatment goal is to reduce these fractures, which cause significant morbidity and mortality.

Hip fractures are the most devastating and can lead to prolonged rehabilitation, permanent disability or death. The use of FDA-approved bisphosphonates can significantly reduce the risk of vertebral and non-vertebral fractures.

A recent study suggests that women who discontinue taking alendronate after five years do not significantly increase their fracture risk for up to an additional five years.12 According to the study, women who discontinued alendronate after five years had the same rate of non-vertebral fractures as women who continued using the drug. However, the study also finds that women who are at a very high risk of vertebral fractures may benefit by continuing to take alendronate beyond the initial five years.¹²

Unfortunately, less than 20 percent of patients with osteoporosis are properly treated or treated at all.³ As healthcare professionals, we should emphasize proper patient selection when considering these medications and educate our patients on the potential benefits and risks.