Home Medizin Genetisches Screening und gezielte Behandlung stoppen die Paget-Krankheit

Genetisches Screening und gezielte Behandlung stoppen die Paget-Krankheit

von NFI Redaktion

A new study suggests that prophylactic treatment with zoledronic acid (ZA) can prevent the development or progression of Paget’s disease of bone (PDB) in individuals with a high genetic risk for the condition. The authors argue that the positive results of the study indicate that individuals with a family history of PDB should undergo genetic screening.

„If it’s positive, you should be able to do a bone scan and take it from there,“ said the lead author Stuart Ralston, MBChB, MD, Professor of Rheumatology at the University of Edinburgh, in an interview with Medical News from Medscape.

Photo of Dr. Stuart Ralston
Stuart Ralston, MBChB, MD

PDB is a chronic skeletal growth disorder affecting an estimated 1–3 million people in the United States, most commonly affecting individuals over the age of 65. The disease symptoms may only appear in later stages when skeletal damage has already occurred and cannot be reversed by medications. Early intervention in individuals who have not yet shown signs of the condition could potentially halt disease progression, said Ralston.

Genetics play a significant role in PDB, particularly with pathogenic variants of the SQSTM1 gene. According to the study, an estimated 40–50% of individuals with a family history of PDB have these variants, which are associated with early onset and a more severe disease.

However, it was unclear whether early interventions in these high-risk individuals could lead to better health outcomes.

In this new study, published on December 20, 2023, in Annals of Rheumatic Diseases, the researchers recruited participants through family members already diagnosed with PDB and receiving outpatient care. Over 1400 individuals with PDB underwent genetic testing for SQSTM1 variants. If they tested positive, the same genetic test was offered to their first-degree relatives—mainly children. A total of 350 relatives tested positive for SQSTM1 variants, with 222 agreeing to participate in the study.

At the study’s outset, all participants received a radionuclide bone scan to look for bone lesions. They were also tested for the bone resorption marker, type I collagen C-terminal telopeptide (CTX), and the bone formation marker, procollagen type I amino-terminal propeptide (P1NP).

Subsequently, the participants were randomized and received either a single intravenous infusion of 5 mg ZA or a placebo treatment. The researchers followed the participants for an average of 84 months (7 years) and then repeated the baseline assessments.

A total of 90 individuals in the ZA treatment group and 90 in the placebo group completed the study.

The participants had an average age of 50 at the start of the study. In the ZA group, nine individuals had lesions identified in bone scans at the start, compared to only one at the end of the study. In the placebo group, 12 individuals had detectable lesions at the outset, compared to 11 at the end of the study.

While the proportion of individuals with lesions in the two groups was similar, the placebo group had approximately twice as many lesions as the ZA group overall (29 vs. 15), which the researchers attributed to chance. Almost all lesions disappeared in the ZA group, compared to 26 remaining lesions in the placebo group (P < .0001).

„The reversal of anomalies in the bone scan was amazing,“ said Ralston, stating that in eight out of nine patients with lesions in the ZA group, „the bone scan evidence was completely eradicated.“ „That is a very strong result.“

Both CTX and P1NP concentrations decreased in the ZA group after 12 months and remained significantly lower throughout the study than in the placebo group (P < .0001 for each).

Overall, the researchers reported that eight individuals in the placebo group and none in the ZA group had an unfavorable outcome, defined as new bone lesions or lesions that remained unchanged or progressed (Odds Ratio 0.08; P = .003). Two individuals in the placebo group developed lesions during the study, compared to none in the ZA group, but this difference was not statistically significant.

Importantly, there were no differences in adverse events between the two groups.

While only a small number of individuals in the study had lesions—approximately 9% of participants—the effect of ZA is „dramatic,“ says Linda Russell, MD, Director of the Osteoporosis and Metabolic Bone Health Center at the Hospital for Special Surgery in New York City, as told to Medical News from Medscape.

Photo of Lisa Russell, MD, director of the Osteoporosis and Metabolic Bone Health Center for the Hospital for Special Surgery
Linda Russell, MD

While doctors primarily diagnose PDB using x-rays or a blood test for alkaline phosphatase, testing for SQSTM1 is a new way to understand if someone is at a higher risk for the disease, she said.

„Now it seems that the test is fairly readily available, so it’s probably something that we can integrate into our armamentarium,“ Russell said.

Individuals who test positive for pathogenic variants of SQSTM1 could then undergo a bone scan, while those who test negative may not need additional testing, she added.

Ralston and co-authors noted that the effect size demonstrated in this study is similar to those of studies investigating adjuvant bisphosphonate therapy in early-stage postmenopausal women with breast cancer. This practice, they write, is now part of the standard of care.

„We believe that a similar approach is now justified in individuals with a family history of PDB who test positive for SQSTM1 mutations,“ they wrote.

However, it is unclear whether all individuals with pathogenic SQSTM1 should receive ZA treatment or if treatment should be limited to patients with bone lesions.

„Future research collecting the views of individuals with a family history of PDB will help determine the most appropriate way forward,“ the authors write.

The UK Medical Research Council and Arthritis Research UK funded the study. Zoledronic acid and a placebo were provided by Novartis. Ralston reported that his institution was funded by Kyowa Kirin, UCB, the Paget’s Association, and the Royal Osteoporosis Society. Some co-authors reported financial relationships with pharmaceutical companies outside of the study. Russell had no relevant financial relationships.

Related Posts

Adblock Detected

Please support us by disabling your AdBlocker extension from your browsers for our website.