Research shows that there is a doubled risk of fractures in patients with acute calcium pyrophosphate crystal arthritis

Researchers will present the first-ever study on fractures and calcium pyrophosphate deposition disease at ACR Convergence 2023, the annual meeting of the American College of Rheumatology (ACR). They report a doubled risk of fracture in patients with acute calcium pyrophosphate crystal arthritis compared with those without the disease (Abstract #0235).

Calcium pyrophosphate deposition disease (CPPD) occurs when calcium pyrophosphate (CPP) crystals form near cartilage cells, sometimes leading to joint inflammation, pain, and swelling. It is often called pseudogout because of its clinical similarity to gout, yet much less is known about CPPD than about gout and other forms of inflammatory arthritis.

Rheumatologist Sara Tedeschi, MD, MPH, her colleagues at Brigham and Women’s Hospital in Boston, and fellow at the Medical College of Wisconsin, wanted to expand the knowledge base by investigating whether patients with CPPD disease are at increased risk for fractures. Previous studies had shown a link between low bone density and CPPD. Recent data from experimental models suggest that increased formation of osteoclast (cells that break down old bone) due to loss of function of osteoprotegerin (a protein that normally inhibits bone resorption) may contribute to the pathogenesis of the disease.

To find out more, Tedeschi and her team conducted a matched cohort study using electronic health records (EHR) from Mass General Brigham’s health care system. The study included more than 1,100 patients who had at least one episode of acute CPP crystal arthritis; the acute inflammatory form of CPPD – between 1991 and 2017. They were compared with more than 3,300 comparison researchers who did not have acute CPP crystal arthritis, although they could have other types of arthritis. The average age in both groups was 73 years, and more than half were women.

The index date for patients with CPP crystal arthritis was either the first mention of pseudogout in their chart or the first synovial fluid analysis with the finding of CPP crystals. The period from registration of the EPD to the index date was at least 180 days. The index date for the matched comparators was a medical encounter within 30 days of the matched pseudogout patient’s index date.

The primary outcome of the study was the first fragility fracture (fractures resulting from a fall from standing height or lower) at the humerus, wrist, hip or pelvis. Secondary outcomes were the first fracture at each of these anatomic locations. For patients with more than one fracture, only the earliest fracture was used. Fragility fractures were identified using published algorithms with a positive predictive value of greater than 90%.

The researchers estimated the incidence rates and incidence ratios for each type of fracture and for fractures at each individual body location. They used Cox models (a statistical technique that can be used to measure time-to-event results on one or more predictors) to estimate adjusted risk ratios for fractures. Patients who had rheumatoid arthritis (RA) or were prescribed corticosteroid or osteoporosis treatment were excluded from the sensitivity analyzes in an attempt to rule out the influence of these diagnoses/medications, which are known to increase the risk of fracture.

The researchers found that the fracture rate was twice as high in the acute crystal CPP arthritis cohort as in the comparison group, after adjusting for traditional fracture risk factors: 11.2 per 1,000 person-years versus 5.6 per 1,000 person-years. The disparity between the two groups increased over time and the sensitivity analyzes yielded similar findings.

Tedeschi says the increased risk of fractures wasn’t particularly surprising, but the difference was large. Also surprising, she says, was “that differences in fracture risk were seen, of similar magnitude, after excluding patients who had used corticosteroids in the 90 days before the index date.” [Moreover]Fracture rates varied within the first months of follow-up, indicating a pre-existing difference in bone health between cohorts.”

Tedeschi notes that the study does not indicate whether patients with acute CPP crystal arthritis had repeat episodes or used corticosteroids after the index date, either of which could influence the findings. She adds that they could not assess falls, which would affect fracture risk and may have differed between CPPD and comparators. She concludes by noting: “The analysis did not assess vertebral fractures as they may be asymptomatic and not captured in diagnosis codes.”

Yet the findings are clear: patients with acute CPP crystal arthritis have a doubled risk of fragility fractures.

“At the very least, we hope that physicians will consider assessing bone mineral density in patients with CPPD to determine whether osteoporosis treatment is necessary,” says Tedeschi.

This research was supported by grants from the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).