Transcript Peroxisomal Biogenesis Disorders and Bone Disease

Eric T. Rush, MD
Clinical Geneticist
Medical Director, Osteogenesis Imperfecta Clinic
Assistant Professor of Pediatrics and Internal
Medicine
University of Nebraska Medical Center
Peroxisomal Biogenesis Disorders
and Bone Disease
Let’s start off with pathways!
Background
• How I got here (the short version)
– As a genetics fellow, I started doing research
through the metabolic bone/OI clinic and
found that I liked it
– Had the rare pleasure of meeting many
families and patients with PBDs in Omaha in
August of 2011 with Drs. Rizzo, Braverman,
and Raymond
Background
• A clear need was expressed by several parents
for treatment of bone issues
• Over the past two years, I have interacted in
some way with several families who are now
being treated
• In recommending treatment, we borrow heavily
from the treatment of other disorders such as
osteoporosis and osteogenesis imperfecta
What is the problem?
1) A number of children with PBD have decreased
bone mineral density and may also have:
–
–
–
–
Bone pain
Fractures
Impaired mobility
Apparently decreased energy
2) There is precisely zero literature on this exact
subject
What isn’t Bone?
What is Bone?
• Cells
– Osteoprogenitor – immature progenitor cells which
differentiate into osteoblasts
– Osteoblast – produces osteoid and then mineralize
that osteoid into mature bone
– Osteocyte – osteoblasts which become trapped in
bone matrix and remain in bone lacunae. Probably
work to maintain nearby bone
– Osteoclast – resorb both the mineral and collagenous
matrix of regions of bone that are damaged
What is Bone?
• Extracellular matrix
– Organic
• 85 - 90% Collagen I
• 1- 2% Osteocalcin
• 8-14% Other proteins and glycosaminoglycans
– Inorganic
• Hydroxyapatite, a calcium and phosphorous
containing mineral
Bone Anatomy
How is Bone Made?
How is Bone Repaired?
Disuse Osteoporosis
• Bone loss due to skeletal unloading
– Neurologic or muscular diseases
– Immobilization, often described in bedridden
patients or with long-term space flight
• Bone loss is regional and correspond to regions
which are not under load
– In non ambulatory patients, we see bone loss
predominantly in femur with relative spinal
sparing
Disuse Osteoporosis
• A negative calcium
balance is observed
in paraplegics and
astronauts prior to
loss of BMD
• Changes to PTH,
Vitamin D, GH,
and sex hormones
have all been
implicated.
Riddle Me This…
• Is disuse osteoporosis
the only explanation for
bone disease in PBD,
or is there something
more?
Bone in Osteogenesis Imperfecta
• “Brittle Bone Disease”
• Mutations to one of the two collagen I genes
lead to either abnormal or insufficient
collagen in the bone.
– Collagen I is 85-90% of the organic matrix of
bone
• Classically leaves bones fragile, shortened,
and bowed
Mild (Mild Nondeforming)
• Straight long bones i.e. no intrinsic long bone
deformity.
• Minimal vertebral crush fractures.
• Absence of chronic bone pain or minimal pain
controlled by simple analgesics
• Normal or near normal growth velocity and height.
• Fully ambulant (other than at times of acute
fracture).
• Lumbar spine bone mineral density Z-score
usually ≥ -2.0
Moderate (Common Variable OI)
• Variable bowing of long bones related to
immobilization for
recurrent fractures.
• Vertebral crush fractures.
• Anterior bowing of legs and thighs.
• Lumbar spine bone mineral density z – score ≤ 2.5.
Severe OI (Progressively Deforming OI)
• Progressive deformity of long bones and spine
(unrelated to fractures).
• Multiple vertebral crush fractures
• Marked impairment of linear growth
• Cases intermediate between severe and extremely
severe have few rib fractures but crumpled long
bones.
Extremely Severe OI
• Continuously beaded ribs due to multiple
fractures by birth.
• Crumpled (concertina-like) long bones.
• All vertebrae hypoplastic/crushed.
• Respiratory distress leading to perinatal death
• Perinatally lethal course
Treatments – Vitamin D
• Vitamin D is not a vitamin, it’s a sterol
hormone!
Effects of Vitamin D
• Vitamin D wants to keep Calcium in the blood
– Increases intestinal absorption of calcium
– Decreases renal elimination of calcium
– Increases resorption of calcium and
phosphorus from bone
• Parathyroid hormone level is regulated by
calcium level in blood, so low vitamin D
causes high PTH
Effects of Vitamin D
• The aim is to keep the Vitamin D level within in
the normal range (30-50 ng/mL)
– Not helpful and likely harmful to have levels much
above 50.
• This will prevent elevated PTH and decrease
bone resorption
• Giving bisphosphonate to people who have very
low Vitamin D levels can predispose to
hypocalcemia
The Bisphosphonate Story
• In the 1930’s, it was discovered that
polyphosphates were able to act as water
softeners by inhibiting calcium salts crystals
• In the 1960’s, it was found that
pyrophosphate exists in the body and it was
hypothesized that this was the body’s own
water softener.
• Initially, the desire was to inhibit abnormal
calcification
The Bisphosphonate Story
• It was hypothesized that a disorder where
pyrophosphate metabolism was abnormal
would be detrimental to bone calcification.
– Indeed this is correct, and the disorder is
called hypophosphatasia
• Early attempts to exploit this discovery were
disappointing because pyrophosphate is
degraded by stomach acid
The Bisphosphonate Story
• Bisphosphonates were one of the experimental
classes devised to be acid stable
– Retained bone mineral affinity
– Inhibited abnormal calcification
• Unexpectedly, the bisphosphonates were found
to stabilize dissolution of hydroxyapatite crystals
– Found that they inhibit bone resorption
• Experimentally found to improve osteoporosis
Pyrophosphate vs. Bisphosphonate
How do they work?
• Bisphosphonates are taken up by osteoclasts
• They directly inhibit a number of enzymes in the
mevalonate pathway, which is in the cholesterol
pathway
– Inhibit production of farnesyl diphosphate (FPP) and
geranylgeranyl diphosphate (GGPP)
• FPP and GGPP are crucial for the activation of
certain proteins that regulate the function of
osteoclasts
Treatments - Bisphosphonates
• First case report of bisphosphonate use in a
patient with OI published in 1987
– Other single cases published in 1997
• First systematic study of thirty children aged
three to six with severe OI and use of
pamidronate published in obscure journal
from Massachusetts in 1998.
• New England Journal of Medicine 1998 Oct
1;339(14):947-52.
• “Administration of pamidronate resulted in … a
mean annualized increase of 41.9 percent in bone
density and the deviation of bone mineral density
improved from -5.3 to -3.4. The cortical width of
metacarpals increased by 27 percent a year. The
mean incidence of radiologically confirmed fracture
decreased by 1.7 per year.”
Treatments - Bisphosphonates
• Dozens of similar studies suggest:
–
–
–
–
Increased density
Fewer fractures
Reduced bone pain
Improved functional status
• Limitations
– Most studies observational, no really large RCTs
– Not sure that it is ethical to do an RCT now
35 Years of Medical, Surgical, and Rehabilitative
Management
Treated from 15 months
Two children with comparable moderate OI, untreated 1975 vs Treated 2010
“Good artists copy, great artists steal”
Pablo Picasso
Caveats with Bisphosphonates
• Known side effects of bisphosphonates
– Fever/flu-like reaction with first infusion
– Hypocalcemia, which can be with any infusion
• Less common side effects
– Osteonecrosis of the jaw
– Bisphosphonate-associated inflammatory
reaction
Caveats for Peroxisomal Disorders
• Side effect profile is much more significant
– Bisphosphonate-associated inflammatory
reaction seems to be more common
• High fever, malaise, low blood pressure
– Vomiting appears to be more common
– Hypocalcemia may be more common
– Have not seen osteonecrosis of the jaw (nor
do I expect to)
Suggestions for Bisphosphonate
Therapy in Patients with PBDs
• Patients should be clinically well for at least
one week prior to infusion
• Labs prior to infusion: Complete metabolic
profile, phosphorus, magnesium, vitamin D
level, urine N-telopeptides
• For initial infusions, patients should be
admitted overnight between the first and
second infusion
Suggestions for Bisphosphonate
Therapy in Patients with PBDs
• For patients with adrenal insufficiency, I would
consider stress dosing steroids during the first
infusion. Acetaminophen and diphenhydramine
should be given
• First dose in the first cycle between 0.125-0.25
mg/kg. Very low.
• Second dose in the first cycle between 0.25-0.5
mg/kg. Still fairly low.
• Ionized calcium after infusions
Suggestions for Bisphosphonate
Therapy in Patients with PBDs
• Venue for subsequent infusions should
depend on the success of the first infusion
– Patients who sail initially should be fine in an
infusion center
• If stress dose steroids are not given prior to
the infusion, providers should have a low
threshold for stress dose later if concerns
develop
Suggestions for Bisphosphonate
Therapy in Patients with PBDs
• Dosage for subsequent infusions
– Less than two years old: 0.5 mg/kg q2m
– Two to three years old: 0.75mg/kg q3m
– Over three months: 1mg/kg q4m
• PBD protocol dose 3 mg/kg
• Omaha protocol dose 4.5 mg/kg/year
• Montreal protocol dose 9 mg/kg/year
Surveillance for Bone Density in
PBDs
• Yearly DEXA while on treatment
• Same labs yearly as the patient had before
infusions, including urine NTX
• Yearly vitamin D with 25-OHD level around
40
• Yearly assessment for well-being and
function by a provider familiar with PBDs
Thanks!
Future scaring major at
Monsters University
Exhausted from watching
big brother
References
•
•
•
•
•
•
•
•
•
•
•
•
Nuttall JM, Hettema EH, Watts DJ. Farnesyl diphosphate synthase, the target for nitrogen-containing bisphosphonate drugs,
is a peroxisomal enzyme in the model system Dictyostelium discoideum. Biochem J. 2012 Nov 1;447(3):353-61. doi:
10.1042/BJ20120750. PubMed PMID: 22849378; PubMed Central PMCID: PMC3465988.
Poll-The BT, Engelen M. Peroxisomal leukoencephalopathy. Semin Neurol. 2012 Feb;32(1):42-50. doi: 10.1055/s-00321306385. Epub 2012 Mar 15. Review. PubMed PMID: 22422205.
Bone H. Future directions in osteoporosis therapeutics. Endocrinol Metab Clin North Am. 2012 Sep;41(3):655-61. doi:
10.1016/j.ecl.2012.05.003. Epub 2012 Jun 28. Review. PubMed PMID: 22877435.
Diab DL, Watts NB. Bisphosphonates in the treatment of osteoporosis. Endocrinol Metab Clin North Am. 2012
Sep;41(3):487-506. doi: 10.1016/j.ecl.2012.04.007. Epub 2012 Jun 9. Review. PubMed PMID: 22877426.
Nagotu S, Kalel VC, Erdmann R, Platta HW. Molecular basis of peroxisomal biogenesis disorders caused by defects in
peroxisomal matrix protein import. Biochim Biophys Acta. 2012 Sep;1822(9):1326-36. doi: 10.1016/j.bbadis.2012.05.010.
Epub 2012 May 19. Review. PubMed PMID: 22617146.
Russell RG. Bisphosphonates: mode of action and pharmacology. Pediatrics. 2007 Mar;119 Suppl 2:S150-62. Review.
Devogelaer JP, Malghem J, Maldague B, Nagant de Deuxchaisnes C. Radiological manifestations of bisphosphonate
treatment with APD in a child suffering from osteogenesis imperfecta. Skeletal Radiol. 1987;16(5):360-3.
Shaw NJ. Bisphosphonates in osteogenesis imperfecta. Arch Dis Child. 1997 Jul;77(1):92-3.
Allgrove J. Bisphosphonates. Arch Dis Child. 1997 Jan;76(1):73-5.
Williams CJ, Smith RA, Ball RJ, Wilkinson H. Hypercalcaemia in osteogenesis imperfecta treated with pamidronate. Arch Dis
Child. 1997 Feb;76(2):169-70.
Aström E, Söderhäll S. Beneficial effect of bisphosphonate during five years of treatment of severe osteogenesis imperfecta.
Acta Paediatr. 1998 Jan;87(1):64-8. PubMed PMID: 9510450.
Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R. Cyclic administration of pamidronate in children with
severe osteogenesis imperfecta. N Engl J Med. 1998 Oct 1;339(14):947-52.
References
•
•
•
•
•
Fu L, Tang T, Miao Y, Zhang S, Qu Z, Dai K. Stimulation of osteogenic differentiation and inhibition of adipogenic
differentiation in bone marrow stromal cells by alendronate via ERK and JNK activation. Bone. 2008 Jul;43(1):40-7. doi:
10.1016/j.bone.2008.03.008. Epub 2008 Mar 29. PubMed PMID: 18486585.
Duque G, Li W, Adams M, Xu S, Phipps R. Effects of risedronate on bone marrow adipocytes in postmenopausal women.
Osteoporos Int. 2011 May;22(5):1547-53. doi: 10.1007/s00198-010-1353-8. Epub 2010 Jul 27. PubMed PMID: 20661545.
Pitts CJ, Kearns AE. Update on medications with adverse skeletal effects. Mayo Clin Proc. 2011 Apr;86(4):338-43; quiz 343.
doi: 10.4065/mcp.2010.0636. Epub 2011 Mar 9. Review. PubMed PMID: 21389249; PubMed Central PMCID: PMC3068894.
Di Martino MT, Arbitrio M, Guzzi PH, Leone E, Baudi F, Piro E, Prantera T, Cucinotto I, Calimeri T, Rossi M, Veltri P,
Cannataro M, Tagliaferri P, Tassone P. A peroxisome proliferator-activated receptor gamma (PPARG) polymorphism is
associated with zoledronic acid-related osteonecrosis of the jaw in multiple myeloma patients: analysis by DMET microarray
profiling. Br J Haematol. 2011 Aug;154(4):529-33. doi: 10.1111/j.1365-2141.
Id Boufker H, Lagneaux L, Fayyad-Kazan H, Badran B, Najar M, Wiedig M, Ghanem G, Laurent G, Body JJ, Journé F. Role
of farnesoid X receptor (FXR) in the process of differentiation of bone marrow stromal cells into osteoblasts. Bone. 2011
Dec;49(6):1219-31. doi: 10.1016/j.bone.2011.08.013. Epub 2011 Aug 26. PubMed PMID: 21893226.2011.08622.x. Epub
2011 Apr 26. PubMed PMID: 21517810.