In 2000 more people started taking the drugs, and reports of side effects began to dribble out, most notably indigestion, a problem solved for many when Merck changed the regimen so that patients took a pill weekly rather than daily (the less often the pills are swallowed, the less they irritate your gullet, and the less vulnerable you are to indigestion). Other emerging side effects were more alarming. Around 2004, Joseph Lane, an orthopedist who’s chief of the Metabolic Bone Disease Service at the Hospital for Special Surgery, began to notice strange events among some patients who’d been taking bisphosphonates for about six years. Two women stand out particularly in Lane’s memory. “One had been complaining of thigh pain for three months,” he remembers. “She’d had two epidural injections for back pain, and while she was in a swimming pool she broke her femur, simply by turning around. Number two is a woman who was getting on a plane to go visit her grandchildren. Similar story: She had earlier complained of sciatica, but her doctors didn’t take an X-ray. Instead, they gave her an MRI and an epidural injection. Then, the day of her flight, she climbed the stairs during boarding and broke her femur going up.”
In 2005, Lane read an article in the Journal of Clinical Endocrinology and Metabolism that jibed with what he’d been seeing. A team at the University of Texas in Dallas and at Henry Ford Hospital in Detroit had biopsied nine patients with osteoporosis or osteopenia, most of whom had been taking alendronate—Fosamax’s generic name—for three to eight years and had “spontaneous nonspinal fractures” in odd places that took an unusually long time to heal. Bone biopsies showed “minimal, or no, identifiable osteoblasts” (the buildup cells) and low breakdown activity—a syndrome that became known in lay language as frozen bone.
This was a small study with no control group, and some patients were taking drugs besides alendronate. But the authors called for more research “to determine how long bisphosphonates can safely be given.” Lane and four colleagues within the New York–Presbyterian/Weill Cornell Medical Center complex reviewed the records of all patients admitted to its trauma center from 2002 to 2007 with femur-shaft fractures that were “low energy,” meaning they had been incurred while the person was simply standing around (or splashing in a swimming pool).
The 70 trauma center patients whose cases they reviewed had all suffered from what’s technically known as an atypical subtrochanteric femur -fracture—and more than a third had been taking Fosamax, the bisphosphonate that’s been available the longest. Three quarters of these Fosamax patients shared a particular radiographic pattern: a simple horizontal or diagonal fracture with a sort of beaky overhang of bone. Their X-rays looked exactly like the one I was presented with two years later. The pattern was 98 percent specific to Fosamax users, and those who displayed it had been using the drug significantly longer than those whose breaks did not look like that. A follow-up study matching a smaller group of patients who had femur fractures with a control group of subjects who had ordinary hip fractures showed roughly similar results: Nearly a third of those with thigh fractures were on Fosamax, as opposed to one ninth of the hip patients; two thirds of the thigh patients on Fosamax showed the pattern, and they tended to have been on Fosamax longer than those with hip fractures.
Meanwhile, more reports were coming out, one from Singapore and one from Japan. Researchers hypothesized that bisphosphonates produce bone that is brittle and fracture-prone and that the thigh pain comes from little stress fractures that don’t heal but rather accumulate and build up to one big kahuna of a break. The patients Lane sees are active women seven to 10 years younger than those who break their hips (which happens on average at age 82). “Every woman I’ve seen has been out there shopping, working, running after her grandchildren, doing stuff,” he says. “These are not couch potatoes. I have never seen this kind of fracture in a nursing home patient.”