麻豆传媒

CHICAGO -- The risk of bone fractures in the hip, spine, and limbs can be markedly reduced by various treatments with bone-strengthening agents such as bisphosphonates, but doctors suggest that these medications are being used less than needed across a vast population that includes both men and women.

"Bisphosphonates, in general, are being underutilized by the people who need them," said Robert Courgi, MD, of the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health's Southside Hospital in Bay Shore, NY.

"If I were speaking from the mountaintop, I would want people to know that osteoporosis is a serious condition and hip fracture is very bad. They need to go get their bone density checked and treat it."

The major problem in getting people on the drugs is that most people who have osteoporosis, who are at risk of falls and fractures and would benefit the most from a variety of these medications, don't realize they need them until they have a fracture, Courgi told 麻豆传媒.

"Osteoporosis is a disease unlike many others in that it is silent. Because it is asymptomatic, many patients and clinicians are not that aggressive in treating it."

"You have to have a primary care physician who is going to prescribe a bone density test, and then the patient has to go get that test and then get a prescription-strength medication, if necessary. And then the patient has to take the medication properly if it is a bisphosphonate or other medications, which can be even more complicated. That requires a lot of steps, and often it is not performed as well as it ought to be."

The bisphosphonates are taken orally – sometimes weekly, or even monthly. The drugs may also be infused on a yearly basis or every 6 months, depending on which agent is prescribed, Courgi said.

Which bisphosphonate fits best is an individual patient/doctor decision. "If someone is low risk and barely meets the criteria for osteoporosis, they could take a medication such as alendronate (Fosamax) for, say, 5 years, and then after 5 years if there is no fracture and they are doing well, they could consider coming off of it. But if someone is at higher risk and has a lower bone density or if they have suffered a fracture, I would have them stay on treatment with a bisphosphonate for 10 years. And then you could consider continuing it beyond 10 years."

"At that point -- either 5 years or 10 years depending on the patient -- I would consider giving them a drug holiday of at least 1 year, maybe 2 years," Courgi said.

"The hard line for the diagnosis of osteoporosis and treatment with bisphosphonates is a bone density of less than -2.5, but anytime a person has a fragility fracture -- a hip fracture, or a spinal compression fracture, regardless of the bone density -- they should start treatment."

A bone density test is recommended for any postmenopausal woman, Courgi suggested. "A bone density test should be done in men over age 80. But the vast majority of osteoporosis occurs in postmenopausal women."

There can be problems with using bisphosphonates for too long, which is why most doctors who treat people with osteoporosis often include drug holiday in their long-term plans, he added.

Using FRAX and DEXA

Caroline Messer, MD, of Lenox Hill Hospital in New York City, explained that long-term use of bisphosphonates can create a situation in which there is too little bone turnover, which can lead to serious subtrochanteric hip fractures. "I tell my patients that once they start on bisphosphonates they are likely to remain on treatment the rest of their lives – but with an off and on pattern," she told 麻豆传媒.

Messer said she depends on the FRAX fracture risk assessment tool along with dual-energy x-ray absorptiometry (DEXA) or bone densitometry, to determine treatment plans. DEXA is the established standard for measuring bone mineral density.

FRAX is a computer-based algorithm developed by the World Health Organization Collaborating Centre for Metabolic Bone Diseases and first released in 2008. The algorithm, intended for primary care, calculates fracture probability from easily obtained clinical risk factors in men and women. The output of FRAX is the 10-year probability of a major osteoporotic fracture and the 10-year probability of hip fracture.

Osteoporosis in Men

While more women than men get osteoporosis, "we have to make it more acceptable [for people realizing] that men get osteoporosis and that men should be treated," said Robert Adler, MD, chief of endocrinology at the McGuire Veterans Affairs Medical Center and Virginia Commonwealth University School of Medicine in Richmond.

He noted that men over age 80 have more fractures than heart attacks, more fractures than strokes, and more fractures than lung cancer and prostate cancer combined. At age 50, the lifetime risk of a fracture in men is 13% to 25%, Adler said. In men over age 80, the mean FRAX score is 37.8%; and 9.2% of men over age 80 have bone density T-scores of less than -2.5, a definite indication of osteoporosis.

Adler said that treatment in men is hindered by a lack of clinical trials in men -- to the point where most information about osteoporosis treatment is derived from studies in women. In addition, men have a more difficult time getting reimbursements for treatments such as bisphosphonates due to that lack of clinical evidence; there are concerns about adverse event of treatment, and in many cases osteoporosis in a man is not recognized until there is a fracture.

Testosterone therapy in men might also reduce the risk of fracture -- even though this remains a controversial area, Adler added. "I personally think that we will eventually show that testosterone helps decrease fracture risk in men. It may be by changes in bone strength, but it also may be by muscle changes and decreasing the risk of falls. It may work for those patients who can take it."

He said that if there was a "level playing field" for treatment -- i.e., if all drugs had a similar cost, could be prescribed without "jumping through hoops," and were given based on best care for the patients -- he would start patients he expected would be on long-term treatment by prescribing anabolic agents such as teriparatide (Forteo) at first and continue that treatment for about 2 years.

The next treatment would be an anti-resorptive agent such as bisphosphonates or denosumab (Prolia) for the next 3 to 5 years.

At the 5-7 year point, Adler would reassess the need for treatment, continuing the prescription for men still at risk and considering a drug holiday for others. "Will this lead to fewer side effects? I can't tell you. Will this lead to fewer fractures? I bet it will." The over-riding question, though, he said: "Will we be willing to pay for it?"

Bisphosphonates in Cancer Patients

Another area where bisphosphonates play a role in protecting bone health is among patients treated for cancer, especially breast cancer. But, said Anthony Elias, MD, of the University of Colorado Denver Cancer Center, Anschutz Medical Campus, in Aurora, bone strengthening is not the only reason for including bisphosphonates in the treatment regimen.

"One reason is preservation of bone density," Elias told 麻豆传媒. "The second would be reduction in fractures and bone pain, and the third potential reason would be to reduce the risk of recurrence."

Preservation of bone density in patients undergoing breast cancer treatment with aromatase inhibitors also requires treatment with bone-strengthening agents, he said. "Aromatase inhibitors are clearly getting rid of estrogen levels and are associated with a decline in bone density, and it is very well documented that bisphosphonates as well as denosumab can prevent that bone loss. It is routine at this point to obtain a bone density, and certainly if somebody already has evidence of osteopenia, there is significant justification to treat that patient with a bone-strengthening agent."

"The National Comprehensive Cancer Network guidelines suggest you should consider treating a women with breast cancer who is going on endocrine therapy with a bisphosphonate because of this evidence for disease-free survival."

"What confounds the discussion, however, is that we don't know how long a person should be on these drugs," he continued. "There is no obvious evidence that a different duration makes a difference in outcome. We don't know which drug to use; we don't know which dosing schedule to use."

Elias said he does use bisphosphonates for his patients who have lower bone density, particularly if he is also prescribing an aromatase inhibitor: "I am agnostic about which one to use or how long to use it. I certainly would want to cover the duration of the use of aromatase inhibitors. We know that generally bone density improves after discontinuing aromatase inhibitors, so I would stop bisphosphonates at the same time. I do consider drug holidays for bisphosphonates, even though there is not a lot of data to support that."

He said that for zoledronic acid or denosumab, he tends to treat patients for 3 years and then give a drug holiday for about a year and then re-evaluate the bone density. "The longer the use of these drugs, the greater the risk of serious complications such as osteonecrosis of the jaw -- most often occurring in people who had dental problems at the beginning of treatment."

And, while bisphosphonates could help reduce fracture risk, most fractures occur because people fall, he said. "[Participating in] exercise programs and balance programs may be more important than whether you give these patients bisphosphonates."

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