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Fractured Body


Ram Gajavelli hit the red “STOP” button on the treadmill, ending his walk at just a quarter of a mile because of the stabbing pain he felt in his feet, legs, and back. The 45-year-old had already delayed a trip to India—originally planned for January 2019—because of his deteriorating condition, and efforts to improve his fitness were constantly derailed by the pain he experienced with every step.

Just two years earlier, shortly after Gajavelli adopted a more active lifestyle, he noticed consistent pain and swelling in his left ankle. An X-ray did not detect any abnormalities in the bone structure, but an MRI a few months later revealed a stress fracture. After months of wearing a walking boot, Gajavelli noticed the pain was growing progressively worse and spreading to different areas of his body, like his back and shoulders. He struggled to climb a flight of stairs, often grabbing the railing to pull himself up. Gajavelli’s oral health was worsening, too—two molars, which appeared fine just nine months earlier, experienced significant decay. Yet, lab tests and scans, ordered by a variety of specialists—from neurologists and orthopedists to rheumatologists and physical therapists—did not reveal any significant abnormalities, leaving Gajavelli still searching for answers two years later.

“I was taking one to two ibuprofen a day and could barely walk,” Gajavelli said. “I had tried everything—a walking boot, cushion in my shoes, exercises to loosen my back. Those provided some relief, but they didn’t solve the problem. Some specialists actually suggested it may just be in my head.”

During his trip to India in February 2019, Gajavelli underwent a bone scintigraphy, a highly sensitive nuclear imaging test used to diagnose and asses the severity of bone diseases. The results showed multiple stress fractures throughout his body—from the metatarsals in his feet to the bones in his jaw. Doctors suggested he was likely suffering from either a metabolic or metastatic issue, and recommended he visit an endocrinologist and hematologist. Upon returning to the United States, Gajavelli visited Ravi K. Amaravadi, MD, co-leader of the Cancer Therapeutics Program at the Abramson Cancer Center and an associate professor of Medicine in the Perelman School of Medicine at the University of Pennsylvania (PSOM). Amaravadi ordered a couple of scans and additional blood tests and sent Gajavelli’s medical history to Mona Al Mukaddam, MD, director of the Penn Bone Center.

Within minutes, Gajavelli received a reply from Amaravadi: “Dr. Al Mukaddam thinks she knows exactly what it is and she wants to see you.”

The Diagnosis

After ensuing biochemical tests confirmed her suspicion, Al Mukaddam diagnosed Gajavelli with tumor-induced osteomalacia (TIO), an extremely rare condition that causes bone pain, fractures, muscle weakness and fatigue. There are between 500 and 1,000 documented case reports of TIO, which is caused by a slow growing small tumor—or multiple tumors–that produces high levels of fibroblast growth factor 23 (FGF23), a protein that decreases phosphorus and active vitamin D levels. Sufficient phosphate is critical for bone mineralization and strength, and is a key component in the process that gives muscle cells the energy to function. In people with abnormally high FGF23 levels, their body eliminates phosphate through the urine, leaving them phosphate-deficient.

“It’s like having the flu and stress fractures throughout your body,” said Al Mukaddam, who has now diagnosed two patients with TIO. “Phosphorus is not a test that is done on routine blood test panels, so one of the most challenging components associated with TIO is thinking of the diagnosis and checking phosphorus. In this case, Gajavelli’s phosphorus levels were never tested during those two years. Once we saw his low phosphorus levels, we conducted additional tests and found his FGF23 levels were abnormally high and that he was losing phosphorus through his urine.”

While the diagnosis provided Gajavelli with a long-awaited answer, the team now faced another difficult challenge: identifying the location of the tumor and then removing it. In many cases, the tumors are very small and difficult to locate. Using an advanced nuclear medicine technique called Gallium-68 DOTATATE PET/CT, the team scanned Gajavelli’s entire body and discovered a 1.4-centimeter wide tumor behind his left hip joint, along with other lesions throughout his body.

“We went back to radiology, reviewed all of the images and determined that all of the other lesions were due to stress factors, not tumors,” Al Mukaddam said. “His condition was being caused by this one solitary tumor.”

Challenges of Surgically Removing the Tumor

3D modeling showing the planned bone cuts (red) and the tumor (green)

While most of the tumors involved in TIO cases are benign, the risk for recurrence is very high, so it’s critically important to surgically remove the entire tumor, Al Mukaddam said. But the location of the tumor can present new challenges.

“Ram is a young patient, so the question was: should we do a complex total hip replacement at such a young age, or is there a way we can preserve his hip without comprising on removing the whole tumor in one piece,” said Robert J. Wilson II, MD, an assistant professor of Orthopaedic Surgery, who performed the surgery on Gajavelli. “From the outset, my discussions with the patient were focused on how we could remove the tumor en bloc and preserve his hip joint.”

“Within 24 hours, the FGF-23 level had normalized,” Wilson said. “Within a week, his phosphorus levels returned to normal.”

Wilson worked with Gajavelli to design a recovery plan to help avoid aggravating or injuring his hip. He advised Gajavelli to avoid putting weight on his leg for the first six weeks following surgery. Within three to six months, he predicted Gajavelli would be off all walking aids and completely back to normal.

“A week ago, on Christmas Day (2019), I walked a mile on the treadmill without any support and didn’t experience any pain,” Gajavelli said. “It’s amazing to look back and think about where I was in early 2019 compared to where I am now.”

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