Osteoporosis Drug May Lead to Atypical Fractures

When the Food and Drug Administration (FDA) approved the drug denosumab (PROLIA) for treating postmenopausal osteoporosis in 2010[1], it was the first time a drug of its kind was to be used for this purpose. Despite the FDA’s ultimate approval of the drug, serious safety concerns had arisen prior to an August 2009 FDA advisory committee meeting discussing issues of safety and efficacy. These safety concerns led denosumab to be categorized as Do Not Use on WorstPills.org.

Denosumab interferes with the body’s important processes of bone metabolism and immune function. One result is that its use may lead to atypical fractures (breaks in the bone that occur spontaneously with little to no trauma, unlike breaks involving major trauma, such as a fall). In November 2012, the drug company issued the first of two warning letters to health care professionals, informing them of the risks of atypical fractures with use of the drug.

Overview of denosumab

It is normal for bones to develop tiny stress cracks, called microcracks, from daily wear and tear. In healthy bone, microcracks are spontaneously repaired by two mechanisms. Cells called osteoclasts naturally break down and remove the damaged bone surrounding the small cracks, and cells called osteoblasts synthesize fresh, new bone.

As some people age, something happens to the tight coupling of the two processes such that the breakdown of bone proceeds at a faster pace than its synthesis. The result is a bone structure that looks more like a honeycomb than a solid mass. When this occurs, the resulting structure lacks its original strength.

The function of denosumab in osteoporosis treatment is to at least partially hinder the overall breakdown process by blocking the work of the osteoclasts. The idea is that this would allow the synthesizing repair process to “catch up.” Yet because breakdown and synthesis of bone are usually tightly coupled, this can have the unintended result that when one process is slowed, the other slows as well.

In the case of denosumab, as noted by the FDA team leader overseeing its evaluation, the drug more strongly affected both the breakdown and repair processes than any drug previously reviewed by that agency, with, at the time, unknown clinical consequences.

One result of denosumab’s function is that in slowing down the natural processes of bone breakdown and resynthesis, microcracks that need to be removed for the bone to be rebuilt are either not repaired at all or are repaired improperly. When the number of unrepaired microcracks becomes large enough, the bone structure is weakened, potentially leading to atypical fractures. In addition, bone structure that has been compromised from the interference with natural breakdown-and-synthesis processes may not be able to heal normally from a break that follows trauma.

Postmenopausal osteoporosis

The drug company submitted to the FDA one pivotal clinical trial of denosumab conducted in postmenopausal women for the treatment of osteoporosis. Women in this trial were between 60 and 90 years of age with a bone mineral density score (T-score) that fell between -2.5 and -4.0 at the lumbar spine and/or total hip[2]. The trial researchers were primarily looking for the appearance of a new, previously unrecognized spinal fracture seen only on X-rays; i.e., a fracture that was unlikely to cause physical discomfort or pain to the patient. Researchers also were looking for nonvertebral fractures (fractures not in the spine) and hip fractures. These would likely cause discomfort or pain to the patient and would then be confirmed by X-ray.

Nearly 8,000 women were randomly assigned to two groups. Each woman received an injection every six months for three years. One group received 60 milligrams (mg) of denosumab, and the other received a placebo. All the women also received vitamin D and calcium supplements.

The absolute changes in the incidence of fracture between those taking denosumab and those taking the placebo were relatively small. After three years, the group given denosumab had 4.8 percent fewer spinal fractures (the ones only seen on X-ray). (That is, over the three-year trial, 7.2 percent of the women in the placebo group and 2.3 percent of the women in the denosumab group experienced a spinal fracture, for a difference of about 4.8 percent.) The reduced risk for hip and nonvertebral spinal fractures was even less: Over three years, women in the denosumab group experienced only 1.5 percent fewer nonvertebral fractures and 0.3 percent fewer hip fractures (the ones causing pain or discomfort) compared to those given the placebo.

Notably, in the group taking denosumab, the incidence of hip fractures increased almost threefold during the third year as compared with the second (0.12 to 0.34 percent). In the group taking the placebo, the incidence of such fractures decreased about 0.1 percent during the same period (0.38 to 0.26 percent).

In terms of new vertebral fractures, the placebo group experienced a 1.6-fold increase during the third year (2.5 to 4.0 percent), while such fractures increased almost threefold in the denosumab group over the same period of time (0.48 to 1.4 percent).

Because hip fractures are responsible for more adverse consequences to women’s health than the other types of fractures, the threefold increase in hip fractures among the denosumab group is noteworthy. The question arises as to whether this increase in hip fractures would continue over time and by how much.

Since denosumab’s initial approval, the FDA has approved the drug to increase bone mineral density in men with osteoporosis facing a high risk of fractures[3], in patients with cancer-related bone disease, and in men and women undergoing certain hormone-related treatments for cancer, without requiring information on its effect on fractures. There is still no approval for the prevention of postmenopausal osteoporosis, although it is possible that the drug gets used in this way since doctors are free to prescribe drugs as they see fit.

Drug safety

As early as its August 2009 advisory panel meeting, the FDA was clearly worried about denosumab’s safety — the result of seeing serious infections, serious dermatologic adverse events and the potential for excess suppression of bone turnover and its effects (e.g., atypical fractures, osteonecrosis of the jaw and delayed fracture healing) in the clinical trial.[4]

It is unusual to find so many serious adverse events established by randomized clinical trials that still result in a drug being approved. Because of the relatively small size of such trials, serious adverse events usually only show up in post-marketing reports when tested in many more people. The FDA’s Division of Epidemiology listed nine “adverse events of special interest” before denosumab’s approval:[5]

• Osteonecrosis of the jaw;
• Atypical fracture;
• Fracture healing complications;
• Hypocalcemia leading to hospitalization or emergency room (ER) visit;
• Infections leading to hospitalization or ER visit;
• Dermatologic adverse events leading to hospitalization or ER visit;
• Acute pancreatitis leading to hospitalization;
• Hypersensitivity reactions leading to hospitalization or ER visit; and
• New primary malignancy.

Given that denosumab affects both normal immune system function as well as normal bone repair, the extensive nature of this list is perhaps unsurprising. What is surprising is that a drug could be approved for use in millions of people with so little efficacy and so many potential serious adverse reactions.

Despite the safety concerns, the FDA approved denosumab in 2010 with the condition that the drugmaker look at administrative databases and conduct a long-term surveillance study in postmenopausal women administered PROLIA to gather more information. Yet these important safety data are already available, obtained from the large randomized, placebo-controlled trial prior to approval that showed that denosumab could cause nine serious adverse events relating to its mechanisms of action interfering with the body’s immune-system and bone-metabolism processes.

Fracture warnings

The occurrence of atypical fractures has already prompted the company to warn physicians. In November 2012, the drug company issued a letter to Canadian health care professionals concerning post-marketing reports of fractures of the thigh, occurring with little or no trauma, in patients taking denosumab.[6], [7]

Subsequently, on Feb. 13, 2013, the company sent another letter, this time to practitioners in the U.K., warning them of “the risk of atypical femoral fracture associated with the use of denosumab” — fractures that occurred in an ongoing clinical trial.[8] No such warning has yet been issued by the FDA to U.S. health care professionals.

An interesting bit of information in the data presented in the company’s original 2008 FDA submission is that a 6-mg dose of denosumab given every three months yielded bone mineral density in the lumbar spine indistinguishable from that of patients given the standard dosage of 60 mg every six months.[9] One can imagine the increase in safety (with comparable efficacy) if that path had been followed.

What You Can Do

The best way to avoid fractures is to engage in regular exercise, since bones respond to an increase in use by becoming stronger. Walking or lifting weights are both good examples of useful exercise. You also should ensure an adequate but not excessive daily intake of calcium and vitamin D (for more on this, see “Vitamin D and Calcium for Bone Health: Getting the Right Amount” in the January 2013 issue of Worst Pills, Best Pills News).

To avoid overdiagnosis, avoid unnecessary screening. Also, remember that bone mineral density is only one of many factors that affect bone strength. Just because your doctor tells you your bone mineral density is low does not necessarily mean you need to begin to take a drug.

References

[1] Highlights of prescribing information: Prolia. Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125320s0000lbl.pdf. Accessed June 4, 2013.

[2] Clinical review addendum for BLA 125320 and 125321 (denosumab). Cross Discipline Team Leader Review, Food and Drug Administration. Page p.16. October 15, 2009.

[3] Highlights of prescribing information: Prolia. Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125320s0051lbl.pdf. Accessed June 4, 2013.

[4] Center for Drug Evaluation and Research: Office director memo from; Julia Beitz, M.D. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125320s000ODMemo.pdf. Accessed June 4, 2013.

[5] Center for Drug Evaluation and Research. Summary review of Prolia. Medical Review; page 4; http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125320s000SumR.pdf. Page 14. Accessed June 4, 2013.

[6] Association of Prolia® (denosumab) with risk of atypical femoral Fracture. Health Canada. http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/medeff/advisories-avis/prof/_2012/prolia_hpc-cps-eng.pdf. Accessed June 4, 2013.

[7] Atypical fractures with an osteoporosis drug (Worst Pills.org e-alert). https://www.worstpills.org/member/ealert.cfm?ea_id=86. Accessed June 4, 2013.

[8] Direct healthcare communication: Risk of atypical femoral fracture with Prolia (denosumab). Amgen. http://www.mhra.gov.uk/home/groups/comms-ic/documents/websiteresources/con241828.pdf. Accessed June 4, 2013.

[9] Highlights of prescribing information: Prolia. Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125320s0051lbl.pdf. Accessed June 4, 2013.