McCune-Albright Syndrome (MAS)
The MAS is a non-inherited, genetic disorder that was first described over fifty
years ago (1). The triad which has classically defined the syndrome consists of precocious
puberty, café au lait skin pigmentation and polyostotic fibrous dysplasia (PFD) of bone (2). Subsequently, it was found that besides
bone, skin and gonads, and a number of other tissues could be involved, predominantly
endocrine tissues such as thyroid (3), adrenal (4), and various pituitary cell populations,
including growth hormone-secreting somatotrophs (5-7). Besides these endocrine tissues,
liver (8), heart (9), and spleen (10) have been found to be affected. Hyperfunctioning
gonads resulting in precocious puberty (11), as well as other hyperfunctioning endocrine
tissues together with PFD account for the majority of the associated morbidity and
are the hallmarks of the presentation and disease course.
The disease presents along a spectrum both in terms of tissues involved, the severity
of involvement and the age at presentation. Sometimes, children are diagnosed in
early infancy with obvious bone disease and markedly increased endocrine secretions
from several glands. At the opposite end of the spectrum, many children are entirely
healthy, and have little or no outward evidence of bone or endocrine involvement.
They may enter puberty close to the normal age, and have no unusual skin pigmentation
at all.
Because of the sporadic occurrence of the disease and the pattern of skin hyperpigmentation,
it was postulated that a genetic defect involving a dominant somatic mutation, occurring
early in embryonic development, may be responsible for the phenotypic presentation.
In 1991, activating mutations of the a subunit of the G protein (Gsa) which stimulates
cAMP formation were described in affected tissues from patients with MAS (12-14).
It is now generally accepted that a somatic mutation occurring early in development
in the Gsa protein is responsible for MAS.
The endocrine tissues most frequently affected in MAS are the gonads (ovaries or
testes), the thyroid and the growth hormone-secreting somatotrophs of the pituitary.
Therapies for hyperfunctioning endocrine tissues include surgical removal of affected
glands or medications directed at hormonal inhibition or blockade. The response is
variable depending on the involved tissue (15-17).
While the skin hyperpigmentation can occasionally be extensive and psychologically
trying for the patient, there are seldom any medical problems associated with it.
Treatment of the PFD is, to date, largely ineffective and this remains the major
therapeutic challenge of the disease.
Current procedures
To date, there is no satisfactory treatment for the crippling, disfiguring lesions
of PFD/MAS. Treatment has included both medical and surgical approaches. Medical
treatment has primarily focused on the use of pamidronate, a second generation bisphosphonate.
Surgical treatment has focused on the use of bone grafts and orthopedic hardware.
Bisphosphonates are a class of drugs with a chemical structure based on pyrophosphates,
the one naturally occurring inhibitor of bone resorption (22). A recent uncontrolled
trial suggested that intravenous pamidronate could reduce bone pain in patients with
severe, symptomatic PFD (23), but objective radiographic improvement was observed
in only a minority of treated patients and it is unclear what the long term effects
of inhibition of bone resorption by pamidronate will be in patients with PFD. An
open label phase III study also reported beneficial effects of intravenous pamidronate
(24). A recently published case report in which a single patient received pamidronate
followed by alendronate, a third generation bisphosphonate, reported a "spectacular"
increase in bone density and a resolution of debilitating bone pain (25).
Fracture of long bones frequently occur in children and adults with FD either in
the monostotic form or the polyostotic form. The fracture may lead to a progressive
deformity such as progressive coxa vara and a Shepherd’s Crook deformity of the proximal
femur. Surgical treatment consist of orthopedic procedures aimed at stabilizing fragile
affected bone that cause pain and/or impaired mobility, and/or resecting regions
of disfigurement or those which impair neural function. They consist of curettage
and/or resection of lesion with and without corrective osteotomy, bone grafting and
hardware fixation devices. The existing methods of surgical treatments are found
to be unsatisfactory. In most cases, there was a recurrence of the lesion, disappearance
of the bone grafting material and separation of the metal fixation devices from the
bone. It was clear that even following these procedures, the deformity progressed
during the post-operative period. The surgical procedure did not affect the long
term frequency of fractures although fracture healing was not impaired. There are
no good fixation devices that would suit young patients with Shepherd’s crook deformity
and there is no surgical procedure that will prevent local recurrence (26-29).
Background: alendronate
Alendronate is a member of the class of drugs known as aminobisphosphonates which
are compounds that are structurally similar to inorganic pyrophosphate. While the
exact mechanism of action is not entirely clear, it is generally believed that as
an analogue of pyrophosphate, it is incorporated into bone. During the remodeling
cycle it is released from bone and through unknown mechanisms inhibits osteoclasts
and thereby blocks active bone resorption. However, there is also some evidence that
bisphosphonates have some activity on the osteoblast. Clinically, the effect is to
reduce parameters of both bone resorption and formation, such as the excretion of
collagen breakdown products and serum osteocalcin. These effects are most clearly
demonstrated in situations of increased bone turnover/remodeling such as in Paget’s
disease or hypercalcemia of malignancy.
Bisphosphonates have been used in the treatment of Paget’s disease of bone and in
the emergency treatment of hypercalcemia in a variety of diseases. Pamidronate is
licensed for use in both indications. Alendronate is approved for the treatment and
prevention of postmenopausal osteoporosis as well as for Paget’s disease. There is
extensive published data on alendronate and other bisphosphonates summarized in recent
reviews (30, 31).
A recent publication looking at the effect of long term treatment (24 - 36 months)
with alendronate at the histomorphometric level was reassuring in that it demonstrated
normal mineralization (32-34).
There are limited data about the use of bisphosphonates in children. Pamidronate
has been used to treat children with cerebral palsy , osteogenesis imperfecta (35)
as well as other diseases (36) (37-39). In addition, other bisphosphonates have been
used to treat a number of other diseases in children (40-42). In general, these drugs
have been safe and effective.
Treatment
Alendronate Dosing
The dosing of alendronate used will be 0.5 mg/kg/d for 6 months, followed by
6 months off drug. The dose will be given orally, once in the morning. This will
be followed by another cycle of 6 months on and 6 months off drug. The on and off
cycle is being used to minimize the possibility of growth plate abnormalities. This
dose and scheduled was arrived at through extrapolation and extension of the recommended
doses and schedules of pamidronate and alendronate used in Paget’s disease and pamidronate
used in PFD. The following ratio was used:
pamidronate in Paget’s = alendronate in Paget’s
pamidronate in PFD alendronate in PFD
This is comparable to the adult dose of alendronate for Paget’s disease of 40 mg
per day. The dose for postmenopausal osteoporosis is 10 mg per day.
Given the limitation of available pill sizes (40, 20, and 10 mg,), the dose stratification
will be as follows:
weight (kg) >50 30-50 20-30
dose (mg) 40 20 10
Dose Modification
The dose of alendronate may be modified if there are significant gastrointestinal
adverse experiences. If these are experienced, the drug will be discontinued for
2 weeks and restarted at _ the original dose. This dose will be maintained for the
rest of the study provided that it is well tolerated. If this is not tolerated, the
drug will be discontinued and the patient withdrawn from this study but offered enrollment
in the screening/natural history protocol.
Risks, Benefits, Hazards and Discomforts
Alendronate
Alendronate is rapidly cleared from the circulation after administration. That fraction
which is not renally excreted in an unmetabolized form is incorporated into bone.
Blood levels following therapeutic doses are below the limits of detection. With
time, that drug which has been incorporated in bone is later released during the
normal remodeling cycle. The terminal half life, including that drug incorporated
in bone is greater than 10 years.
Animal testing showed that rats receiving high doses developed parafollicular thyroid
adenomas. In vivo and in vitro mutagenesis studies were negative with
the exception of the following: a weakly positive response at concentrations >
5 mM in cytotoxicity in in vitro chromosomal aberrations in Chinese Hamster
ovary cells. There was no effect on male or female fertility in rats given 4 times
the equivalent human dose. Fetal abnormalities were observed in fetal rats but not
rabbits when high doses were given to the pregnant mothers.
The risks of the use of alendronate in children are unknown. There is only one published
report of the use of alendronate in children. It involved the treatment of 4 children
with glucocorticoid-induced osteoporosis (43). The drug was safe and effective. Specific
concerns about the safety of alendronate will have to be extrapolated from the studies
of other bisphosphonates in children. This subject has recently been reviewed and
while inconclusive, the findings are reassuring (40-42). There are approximately
25 published reports of the use of bisphosphonates in children. The greatest theoretical
concern was that by inhibiting bone turnover and disrupting the remodeling process
there would be bone deformity and disruption of the mineralization process. The evidence
so far is that this does not occur.
A specific observation that has been made in the use of pamidronate was of a widening
of the growth plate that resolved when treatment was discontinued (23). In children
with fibrodysplasia ossificans progressiva treated with etidronate there was and
increase in translucent area in bone (44). Transient symptomatic hypocalcemia occurred
with intravenous pamidronate (45). Undertubulation at the growth plate has been reported
with the use of pamidronate without any evidence of bone deformity after treatment
is discontinued (46). A number of eye problems (anterior uveitis, episcleritis, and
transitory conjunctivitis) have been reported with pamidronate, but only when used
intravenously (47-50).
The major side effects reported with alendronate in studies involving adults were
gastrointestinal, and most of those were mild and dose-related. Those adverse effects
reported that were greater than placebo were: abdominal pain (6.6%), dyspepsia (3.6%),
constipation (3.1%), and diarrhea (3.1%). While there has been much concern about
alendronate causing severe esophagitis, when patients in studies (n=597) were compared
to controls (n=397), there was no greater incidence of esophageal problems. Mild
and transient decreases in calcium (18% of patients) and phosphate (10%) were observed.
However, clinically significant decreases in calcium (<8 mg/dl) and phosphate
(<2 mg/dl) were the same in treatment and placebo groups.
Alendronate can cause secondary hyperparathyroidism. The probable mechanism is through
decreasing serum calcium and thereby stimulating PTH release. The risk of this occurring
can be decreased through the addition of supplemental calcium and vitamin D in the
diet. Patients will be monitored as well as prescribed a weight-appropriate dose
of calcium supplementation and vitamin D in the form of a multivitamin.
Reports of the impact of alendronate on reproduction in humans are lacking. Studies
in rats show drug use during gestation may have maternotoxic effects and cause neonatal
death when administered during gestation. Pharmacokinetic studies demonstrate that
approximately 2/3 of the drug is eliminated unmetabolized in the urine within 6 months
of stopping treatment. A bone biopsy study showed that there is no effect on mineralization
(33). It is classified by the FDA as Pregnancy Category C and its use during pregnancy
is not recommended.
Bone Biopsy
The bone biopsy will be performed under local anesthesia in adults and adolescent
patients, and light general anesthesia in young children by one of the investigators
who is has been deemed qualified to do so. The biopsy is performed through a small
skin incision which is closed with 2-3 stitches that will dissolve within 2-3 weeks.
The site of the biopsy may cause discomfort and pain for several days and can be
treated safely with acetaminophen. Bleeding and infection at the site of biopsy are
possible but rare. A skin biopsy will be performed at the time of the bone biopsy.
The skin biopsy adds no additional risk or discomfort to the procedure.
Other risks associated with the study
1. Needle stick may cause pain. This can be alleviated by preapplication
of a local anesthetic creme or gel (EMLA).
2. The total absorbed radiation per site is detailed in appendix 7, NIH Form
88-23. The usual dose permitted for research purposes in adults is 3 rem to any tissue
in a 13 week period and 5 rem in one year. The dose for children is 1/10 that dose.
The total dose to be received in this study exceeds this amount. This is largely
due to the amount of exposure form the Tc-99m MDP bone scan. However, the bone scan
is a clinically indicated study that should be performed in the appropriate diagnosis
and management of all patients with PFD.
3. Procedures done under general anesthesia carry the risk of cardiac arrest,
brain damage or death. Pneumonia may occur following general anesthesia. Patients
with conditions other than MAS/PFD will not be enrolled into the study in order to
minimize this risk.
4. Tetracycline labeling (domeclocycline) may cause staining of teeth in young
children. Children over the age of six years are unlikely to have staining since
their secondary teeth are already formed within the gums. In the summertime, tetracycline
can cause rashes due to sensitizing the skin to sunlight. This can be prevented by
use of sunscreens or appropriate protective clothing.
5. Blood withdrawal poses a very small risk due to depletion of blood volume.
By staying within the NIH weight-based guidelines the possibility of this occurring
is very remote
Potential Benefits
Patients will undergo extensive evaluations while enrolled in this study. It
is possible that as a result of these evaluations previously undetected conditions
or problems may be detected. This knowledge may be of benefit to the patient.
When appropriate, NIH physicians will offer treatment for these newly detected conditions
to the patient. When treatment by NIH physicians is not appropriate or possible,
the information and results of testing will be conveyed to referring physicians.