Asymptomatic Paget's disease — To treat or not to treat
Paget's disease of bone is a focal disorder of bone remodeling. The disease may involve a single bone or multiple bones and has a predilection for the axial skeleton, such as the pelvis, femur, spine, skull and tibia. The diagnosis of Paget's disease is usually based on radiographic findings that are characteristic of this disorder, including:
- Focal osteolytic lesions
- Coarsening of the trabeculae
- Cortical thickening and enlargement of the bone
A whole-body bone scan is frequently performed when Paget's disease is diagnosed to establish the extent of the disease.
Robert D. Tiegs, M.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic in Rochester, Minnesota, says: "Individuals with Paget's disease are usually asymptomatic, but may present with bone pain, bowing deformities of the long bones, fractures or nerve compression syndromes. The clinical features depend on the activity of the disease and the severity and location of the bony deformities.
"Although much has been learned about the epidemiology, clinical features, natural history and genetics of this disorder since it was described by Sir James Paget in 1877, there is disagreement about the need to treat individuals who have asymptomatic disease. In an article that appeared in the New England Journal of Medicine in 2013, Professor Stuart Ralston stated, 'There is no evidence that asymptomatic patients benefit from anti-resorptive therapy.'
"The guidelines published by the Bone Research Society of the United Kingdom reflect this view. According to these guidelines, the only indication for the use of anti-resorptive drugs is pain caused by an increase in the metabolic activity of bone. Treatment of asymptomatic patients was not recommended because treatment has not been shown to prevent complications. The results of the PRISM trial have been cited to support this approach."
The Paget's Disease: Randomized Trial of Intensive Versus Symptomatic Management (PRISM) trial studied 1,324 people with Paget's disease in the United Kingdom. Dr. Tiegs explains, "This trial did not show a difference in fracture, the need for orthopedic surgery or hearing loss when comparing the outcomes of patients who received intensive therapy to patients who received symptomatic therapy during the two to five years that patients were monitored."
In an editorial in the same journal, Professor Ian Reid outlined the limitations of the study:
- Most patients had been treated with bisphosphonates prior to enrollment in the study.
- More than half of the participants had normal serum alkaline phosphatase values at the time of entry into the trial.
- The difference in disease activity between the two groups was small (78.8 percent of the patients in the intensive treatment group had normal serum alkaline phosphatase levels at the end of the study, compared with 61.2 percent of the patients in the symptomatic treatment group).
- Zoledronic acid, which has been shown to be more effective than risedronate for the treatment of Paget's disease, was not available when the study was designed.
- The study was not designed to assess the effect of the different treatment approaches on fractures through pagetic bone.
- The duration of the study was short relative to the time required for complications to develop.
"The PRISM trial contributed to our understanding of Paget's disease and its treatment, but did not address the question of whether treatment early in the course of the disease reduces the risk of long-term complications," says Dr. Tiegs.
An alternative approach is to treat asymptomatic patients who have active disease involving skeletal sites where complications are likely to develop, such as the skull, spine and long bones. Dr. Tiegs argues that the support for this approach is based on several observations.
First, bone deformities progress in untreated patients with Paget's disease and can cause serious complications, including:
- Bowing of the long bones, which predisposes to secondary arthritis and fracture
- Softening and enlargement of the skull
- Neurological compression syndromes, including spinal stenosis
Second, treatment with the new generation of nitrogen-containing bisphosphonates has been shown to:
- Promote healing of osteolytic lesions
- Restore bone remodeling to normal levels in a majority of patients
- Improve bone histology through the formation of lamellar rather than woven bone
The adverse reactions to the nitrogen-containing bisphosphonates, such as atypical femur fractures and jaw osteonecrosis, also need to be considered when prescribing these agents. The frequency of these complications may be less in patients with Paget's disease, because:
- Treatment is intermittent
- Doses used to treat patients with Paget's disease are less than the doses used to treat patients with skeletal metastases
- Based on our knowledge of the pharmacokinetics of bisphosphonates, the drug is preferentially delivered to areas that have the highest rate of bone remodeling — pagetic bone
Dr. Tiegs concludes: "We do not have evidence that treatment with anti-resorptive agents alters the natural history of the disease, prevents skeletal deformities or reduces the risk of complications that result from these deformities. Until we have better data, the decision to treat or not treat asymptomatic patients should be based on clinical judgment and patient preferences."
For more information
Ralston SH. Paget's disease of bone. New England Journal of Medicine. 2013;368:644.
Langston AL, et al. Randomized trial of intensive bisphosphonate treatment versus symptomatic management in Paget's disease of bone. Journal of Bone and Mineral Research. 2010;25:20.