SHARE
Bisphosphonate Use for Individuals Living with OI
Bisphosphonate therapy, such as intravenous pamidronate or zoledronic acid, has become a standard treatment to increase bone density, especially in children with moderate and severe osteogenesis imperfecta. In most of the studies of people living with OI, bisphosphonates led to a beneficial increase in bone density (measured by DEXA scan). Determining when to start, the most effective dose, and how long to treat are issues that continue to be studied.
What is a Bisphosphonate?
Bisphosphonates are a group of medicines that are used to slow down normal bone breakdown, allowing bone mass to increase. There are several versions of bisphosphonate compounds, which vary based on the mode of administration and potency. The commonly used versions of bisphosphonate therapy in OI can be broken down into two categories:
- Intravenous (IV) Administration
- Pamidronate (Aredia®)
- Zoledronic acid (Zometa®/Reclast®)
- Oral Administration*
- Alendronate (Fosamax®)
- Risedronate (Actonel®/Atelvia®)
Bisphosphonate Therapy in Children vs. Adults
It’s unclear whether children and adults respond differently to bisphosphonate therapy. Early treatment studies in children with OI have reported an increase in bone density, an increase in cortical bone width, a decrease in cortical bone porosity, and a reduction in bone pain. It is still controversial as to whether this also results in a decrease in the number of fractures. There are fewer studies in adults with OI, but those available suggest that bone density improves with bisphosphonate therapy in adults with OI. The effect on fracture risk in adults is unclear.
Oral bisphosphonates are typically not used with children as they appear to be less effective, and compliance more difficult to maintain. In general, growing children seem to have more rapid changes in bone density in response to drug therapies, and more rapid bone turnover in children means that IV bisphosphonate treatments are given more often.
Treatment with Bisphosphonates
There are several main cell types in the bone. Two of the most important are osteoblasts and osteoclasts. The osteoblasts make bone (bone formation) and the osteoclasts break down bone (bone resorption). The balance between the osteoblast and osteoclast determines whether bone mass increases, is stable, or declines. Both types of cells are very active throughout life and ideally work together to promote bone growth in kids and to keep the bone intact in adults. Current knowledge suggests that bisphosphonates slow down the process of bone resorption by shortening the life of the osteoclasts and reducing how much bone they break down, thus tilting the balance towards the production of bone. In people with OI treated with a bisphosphonate the osteoblasts still produce mutant collagen. Thus, the patient is still making “OI bone,” but resorbing less of it.
Some animal studies of bisphosphonate treatment have shown that the femurs are less elastic (in other words, they have less capacity to bend before they break), which would not be desirable in people with OI. Whether this effect seen in animal studies is important in people with OI treated with bisphosphonates is uncertain. It is also not clear at this time whether the bisphosphonates will have the same effects on the spine, which is mainly trabecular bone, and the long bones, which are mainly cortical bone.
Metabolism of Bisphosphonates
Bisphosphonates are not metabolized (broken down) in the body. Fifty percent of the medication goes directly to the bone, and 50 percent is excreted in the urine. Current studies are just beginning to measure how long bisphosphonates remain in the body, which will affect how often treatment is administered. In children, treatment is typically repeated every 3-6 months for iIV bisphosphonates, and weekly for oral bisphosphonates. In adults, treatment with IV bisphosphonates is less often, for instance once per year for zoledronic acid.
Administration of Bisphosphonates
Pamidronate is given by slow IV infusion over 3-4 hours. Treatment is usually given once/day for 1-3 days. In South America and Europe, pamidronate is also available for oral administration. Zoledronate is given by a rapid IV injection of approximately 10-30 minutes. Alendronate (Fosamax®) and risedronate (Actonel) are given by mouth, and can be given as a daily pill or a larger weekly dose. Current directions for oral bisphosphonates include specific guidelines regarding taking it first thing in the morning on an empty stomach, at least 30 minutes before eating or laying down. The weekly dose appears to provide similar benefits to the daily regimen, but with less gastrointestinal discomfort.
Short-term and Intermediate-term Side Effects of Treatment with Bisphosphonates
One short-term side effect reported by the Shriners Hospital for Children, in Montreal, Quebec, Canada, after treating more than 200 children with IV pamidronate is a flu-like syndrome, including fever, during the first day after the first treatment. Some children have decreased blood cells, which return to normal values in 48-72 hours.
A more recently reported intermediate-term side effect, reported by groups in both Canada and Australia, is slow bone healing after an osteotomy. The Australian researchers have discontinued use of bisphosphonates for several months before surgeries in which osteotomies will be required.
Persons taking oral alendronate or risedronate can have gastric discomfort or irritation of the esophagus (the tube connecting the mouth with the stomach) if the drug is not taken properly or if the individual has a history of gastric disturbance (such as ulcer or gastric reflux). Additional problems that have been seen in adults and described in medical literature include muscle pain, eye irritation and headaches.
There is some evidence, although inconclusive, that bisphosphonates may cause birth defects if taken at the time of conception or during pregnancy. There is no evidence that they affect fertility in people who have been taking them.
Dental Health and Bisphosphonates
In osteoporosis,bisphosphonates have been associated with a very rare side effect called osteonecrosis of the jaw. At this time, there is no evidence that bisphosphonates cause more frequent dental problems in OI. They do not improve dentinogenesis imperfecta (DI) when the treatment is started after three years of age. Whether bisphosphonate treatment for infants will lead to a reduction in the seriousness of DI is under investigation. There is some concern that bisphosphonates might decrease the effectiveness of orthodontic treatments, but this is only beginning tobe studied.
Q & A about Bisphosphonate Therapy
Could bisphosphonate therapy improve any of the other problems associated with OI?
OI is caused by a defect in Type I Collagen. Besides fragile bones, this defective collagen causes loose joints, muscle weakness and various degrees of short stature in most persons with OI. To date, there is no evidence that any of the bisphosphonates encourage growth, but neither do they seem to inhibit normal growth in children. Loose joints and tendon problems are not affected by bisphosphonate treatment.
Some literature suggests that this therapy can be useful for the management of scoliosis in people who have OI, but this is still uncertain.
What is the difference between intravenous pamidronate treatment and intravenous zoledronic acid treatment? The first bisphosphonate used in children with OI was IV pamidronate, which requires a 1-3day infusion every 3-4 months. Zoledronic acid is also given intravenously but only requires one 30-60 minute infusion every 3-6 months. Zoledronic acid has slightly different characteristics including greater potency. For convenience, zoledronic acid treatment is considered advantageous due to a smaller volume of IV fluid required, shorter infusion times, less chance of reactions during the first infusion, and less frequent infusions. In adults, pamidronate is rarely used and zoledronate is usually administered no more than once/year.
How long might a person with OI need to stay on bisphosphonate treatment? DEXA bone scans and blood tests will help plan the dose and duration of treatment. While some individuals taking bisphosphonates on various research protocols are reported to have reached average bone density, it is not possible to predict how any particular individual will respond to the drug. When some of these individuals were taken off bisphosphonates, their bone density gradually decreased over several years. However, it is also important to note that increased bone density does not necessarily translate into increased bone strength. Furthermore, bone density is just one aspect that is modified by the drug – some people report pain relief after bisphosphonate therapy.
Should treatment be discontinued for an osteotomy or a fracture? Scheduled bisphosphonate treatments should not be adjusted in the case of a fracture, but they might around an osteotomy. The drug can be safely administered up to two days before surgery because medication has then cleared from the bloodstream. Reactivation of treatment should be timed with the healing of the osteotomy site- usually 4-5 months- but it may vary due to bone turnover activity.
Decision on continuation of treatment or changing to a lower dose regimen is the responsibility of the treating physician and should be made on a case-by-case basis. It is recommended to discontinue treatment when growth is completed.
What is the role of Physical Therapy, and/or nutritional supplements for a person receiving bisphosphonate therapy?
Studies of osteoporosis show that bisphosphonate therapy is likely to be most effective when accompanied by adequate calcium/vitamin D nutrition and and an adequate exercise program. An exercise program is always beneficial for people with OI.
Since research is on-going, what isn’t known about bisphosphonate therapy?
Studies of bisphosphonates have focused on conditions such as osteoporosis that primarily affect older adults. Researchers who are familiar with OI are posing a number of questions including the following:
- Are there any long-term negative side effects?
- Will changes in bone density lead to significant improvement in bone strength and fracture risk?
- Does bisphosphonate treatment change the composition of the matrix of OI bone?
- Do bisphosphonates affect the bone of the spine differently than the long bones in legs and arms?
- What is the role of physical therapy in the bone density improvement that may occur?
- What may be the most effective dosage, and mode of administration for persons with the different types of OI and for persons of different ages?
Since the bisphosphonates are an investigational drug for OI, persons with OI who are interested in receiving a member of this drug family are encouraged to do so as part of a research program. In general, research programs will have more experience with the use of the drug and the knowledge gained can benefit other persons with OI.