T. Klein, President and CEO
National MPS Society
J. Noble, Vice Chair ISMRD
Children with Mucolipidosis (ML) have many issues with chronic pain that may result in loss of mobility, sleep disturbances, loss of concentration, chest infections, and a general feeling of being unwell. Quality of life can be severely compromised by the age of 8 to 10 years. Families report a noticeable decline in mobility, an increase in pain and stiffness, as well as difficulty in their ability to complete day to day tasks. Bone density testing with Dexa Scans as well as blood and urine tests in these children commonly demonstrate a significant loss in bone density known as osteopenia, or in its more severe form, osteoporosis.
In a select group of children and young adults in Australia, New Zealand, and United States, Pamidronate treatment has provided a dramatic improvement in mobility, well-being, and general physical ability. Some of these children are reporting that they have no pain at all, and others are reporting that they have significantly less pain. Families who took part in the initial study were reporting that there was a reduction in chest infections. This may be due to the ability to cough without pain.
Rationale
Bisphosphonates are a class of drugs now being widely used in the treatment of osteoporosis, and in the treatment of bone related pain in other lysosomal storage diseases, such as Gaucher disease.
Traditionally, Bisphosphonates are used to decrease bone resorption by inhibiting normal bone metabolism, thus allowing an increase of normal bone mass and balance to occur. Anecdotally, many individuals have reported a dramatic decrease in pain as well.
The Bisphosphonate being used in patients with ML is called disodium Pamidronate. (Pamisol/Aredia). In ML, the Bisphosphonate, appears to have a beneficial clinical effect which results in decreased bone pain, increased mobility and reversal of some ML bone pain related symptoms.
Indications
The treatment of patients with Pamidronate is experimental, and at present, it is hoped that its use will be investigated as part of an international multi-center collaborative study. Before patients begin therapy, the benefits should be weighed against the known and potential side-effects (see Adverse Reactions below).
Because this is an experimental therapy, strict guidelines for the use of Pamidronate have been established. This therapy could be considered in individuals with ML III in whom there is clinical and radiographic evidence of progressive bone loss, documented osteopenia, or at any stage of the disorder where activity related pain has become a significant detriment to quality of life and may be attributed to bone disease. In individuals with ML II, treatment may begin after resolution of the secondary neonatal hyperparathyroidism (usually after 3 months of age), if there is progressive osteodystrophy and in whom suitable intravenous access can be established.
Baseline tests
There are many baseline tests to be done prior to commencing the first infusion of Pamidronate. These tests include blood work, imaging and urine tests, and are important for establishing the need for Bisphosphonate therapy and for tracking the effectiveness in each individual. These tests are outlined in the guidelines for treatment, which are available at www.mpssociety.org
• Auxology (hearing tests) Dexa Scan
• Full Skeletal Survey
• Bone Age (Left wrist and hand) Lateral Spine (AP if Scoliosis) Renal Ultrasound
• Serum Calcium
• Serum Phosphate, Alkaline Phosphatase Vitamin D metabolites
• Serum Osteocalcin
• Urinary Deoxypyridinoline cross-linking
• Other tests as outlined in the guidelines for Pamidronate treatment in ML
Dose
Dosing regimens have been established, and should be discussed with your treating physician.
Adverse Reactions
Some children will have “flu like” symptoms (i.e. fever, nausea, vomiting, headache, and body aches and pains) which usually occur following the first infusion, within the first 12 to 24 hours, and generally subside within 48 hours. With subsequent infusions these symptoms do not usually occur but if they do, it is to a lesser degree. Some children have reported general aches and pains lasting up to seven days. Two children reported having sore feet.
Other reported side effects are disturbances in blood electrolytes such as calcium, phosphate, potassium and magnesium, decreased white blood cell counts and anemia, and difficulties controlling fluid balance and blood pressure. Most of these side effects can be easily monitored and treated.
Additionally, after market studies have demonstrated the development of osteonecrosis of the jaw bone, which is loss of bone vascularity in the jaw leading to loose teeth, sharp edges of exposed bone or bone spurs, or breaking loose of small bone spicules or dead bone. This has been primarily described in older patients with cancer, using a treatment/protocol that is more aggressive in therapy and dose than the protocols followed with mucolipidosis patients. The protocol for ML II/III is of a lower dose infused over a longer period of time. It is noted that the patients who have been on treatment for five years are not showing the above problems, but should be kept in consideration while taking pamidronate.
Ibuprofen and acetaminophen (Tylenol) can be given to help with this initial pain. It is recommended that the children be admitted to the hospital for the first two infusions to monitor these “flu-like” symptoms.
As always, it is recommended that families seek further information and advice from their doctors.
Endpoints
At this time there are no end points for treatment. It is acknowledged that an international multi-center collaborative trial is needed, which in turn will produce definite guidelines that can be made available for treating physicians.
The questions being posed now are: What do we do when the children/young adults reach normal bone density range and are almost pain free or are pain free?
There are children in Australia and New Zealand moving on to trial other types of bisphosphonates either by the oral route, or by continuing with IV treatment given at longer intervals. The ultimate goal of this treatment is to keep the children and young adults pain free so that they continue to have quality of life.
References
The following references and papers are available to download from ISMRD www.ismrd.org
Robinson, C ; Baker, N; Noble, J; King, A; David, G; Sillence, D; Hofman, P; and Cundy, T; The osteodystrophy of Mucolipidosis type III and the effects of Intravenous Pamidronate treatment, J. Inherit, Metab, Dis, 25 (2002) 681-693
Sillence, D. MD FRACP Sydney Australia, “The Value of Cyclic Intravenous Pamidronate in Mucolipidosis Advantages and Disadvantages”
http://www.mannosidosis.org/library/ BISPHOSPHONATE THERAPY IN MUCOLIPIDOSIS – 342.doc“
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