Nutritional CAM Proposal for Osteogenic Imperfecta Osteogenic Imperfecta Adjunctive CAM Therapies A Novel Proposal for Adjunctive Complimentary Alternative Medicine Nutritional Therapies for Osteogenic Imperfecta Kimmer Collison-Ris MSN, FNP-C, WOCN Master Science Complimentary Alternative Medicine Candidate NAT: 501 April 30, 2012 American College of Healthcare Sciences Abstract 1
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Novel CAM Therapies in the Management of Osteogenic Imperfecta
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Nutritional CAM Proposal for Osteogenic Imperfecta
Osteogenic Imperfecta Adjunctive CAM Therapies
A Novel Proposal for Adjunctive Complimentary Alternative Medicine Nutritional
Therapies for Osteogenic Imperfecta
Kimmer Collison-Ris
MSN, FNP-C, WOCN
Master Science Complimentary Alternative Medicine Candidate
NAT: 501
April 30, 2012
American College of Healthcare Sciences
Abstract
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Nutritional CAM Proposal for Osteogenic Imperfecta
Osteogenic Imperfecta (OI) is a rare systemic heritable disorder commonly known as
“brittle bone disease”; whose cardinal manifestation is bone fragility resulting from
collagen and connective tissue weaknesses. In approximately 90% of individuals with
osteogenesis imperfecta, mutations in either of the genes encoding the pro-α1 or pro-α2
chains of type I collagen (COL1A1 or COL1A2) can be identified (Basel and Steiner
2009). Some media attention has recently portrayed the severe forms of the disease (type
2) but often persons possessing types I, III, and IV often receive delayed diagnosis due to
under recognition and shared features with other common childhood medical conditions.
The current standard of care includes a multidisciplinary approach with surgical
intervention, proactive physiotherapy, and the use of bisphosphonates; all in attempts to
improve quality of life. Although drug therapy, surgery and physiotherapy represent
current treatments for OI, the search is ongoing for effective and innovative new
therapies targeting the underlying causes of the disease (Millington-Ward, McMahon and
Farrar 2005).
There is evidence to substantiate the use of Complimentary Alternative Medicine
nutritional therapies as valid and supportive adjunctive treatments in other bone and
connective tissue conditions (Osteoporosis, Osteomalacia/Rickets, Osteoarthritis, and
Osteopenia due to Cystic Fibrosis). Providers and patients attest to the significance of
nutritional medicine and the addition of CAM therapies to improve quality of life in these
individuals. This writer believes that these medical conditions share similar features with
the milder forms of Osteogenic Imperfecta and might be used as models to serve as
adjunctive CAM therapies to these individuals. The purpose of this paper was to propose
Adjunctive Complimentary Alternative Medicine (CAM) Therapies for persons affected
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Nutritional CAM Proposal for Osteogenic Imperfecta
with OI, to infer dietary and supplements therapies that might strengthen bones/teeth and
relieve associated symptoms caused by this collagen/connective tissue disorder.
This writer reviewed research and treatments for osteoporosis, osteoarthritis,
osteomalacia, and Cystic Fibrosis to propose novel adjunctive CAM nutritional and
dietary therapies for persons with OI. Greater than 95 abstracts on nutritional
recommendations influencing bone, muscle, and connective tissue in adolescents and
adults were obtained and tables were created to assess common themes in the findings.
Several variables of interest were: nutrients that positively or negatively strengthened
bones and connective tissue, types of nutritional supplements, alternative pain relief
methods, growth and development needs, and risk factors with current conventional
therapies, and influencing dietary interventions. Out of all the abstracts and papers
studied, no one paper proposed specific nutritional therapies for strengthening bones and
connective tissues or provide pain relief in persons with any form of OI. However, this
writer saw evidence that supported dietary and nutritional adjunctive CAM therapies for
treatment in persons with OI, and concluded that the dietary and nutritional guidelines for
Osteoporosis, Osteoarthritis, and Osteomalacia, Cystic Fibrosis related Osteopenia,
connective tissue, and immune health could serve as models for specific OI interventions.
To date, no such paper has been published using this proposal. Due to large number of
OI health issues and symptoms, specific details can be found in the various tables
included.
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Nutritional CAM Proposal for Osteogenic Imperfecta
Introduction
Osteogenic Imperfecta (OI) is a rare genetic disorder commonly known as “brittle
bone disease” that presents with variations of severity. Recent attempts have expanded
the classification of this disorder from types I-VIII with types I-IV being the most
common and type II being commonly fatal in infancy (see OI Types Table 1).
Currently there is no known cure for Osteogenic Imperfecta. Persons suffering from this
disease experience a variety of symptoms that range from mild in severity to quite severe
and debilitating (see OI symptoms & Dietary Supplement Recommendations Table 3).
Although there is no known cure and conventional treatments focus largely on surgical
repair, physical therapy, and medication management; strategies to improve nutrition and
nutrient deficits remain under-investigated and are not mentioned within the literature.
Providers and patients attest to the significance of nutritional medicine and the
addition of CAM therapies impacting quality of life in individuals with bone diseases.
This paper proposes adjunctive Complimentary Alternative Medicine therapies for the
relief of many of the symptoms of mild to moderate Osteogenic Imperfecta. Models for
Osteoarthritis, Osteoporosis, Osteomalacia, and fracture healing are utilized in this paper
and infer benefit to clients with OI (refer to Table 3). This writer believes that these
medical conditions share similar features with the milder forms of Osteogenic Imperfecta
and might be used as models to offer CAM therapies to these individuals.
Osteogenic Imperfecta
Osteogenesis imperfecta is a systemic heritable disorder of connective tissue resulting
from deletions, insertions, or exon splice errors in the genes encoding type I collagen pro-
α1 and pro-α2 chains (Weis, Emery, Becker , n.d.) whose cardinal manifestation is bone
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Nutritional CAM Proposal for Osteogenic Imperfecta
fragility (Basel and Steiner, 2009). Although drug therapy, surgery and physiotherapy
represent current treatments for OI, the search is ongoing for effective and innovative
new therapies targeting the underlying causes of the disease (Millington-Ward,
McMahon and Farrar, 2005).
In most cases, the mutation is unknown and diagnosis is made by clinical assessment
of symptoms, which include bone fragility, defective skeletal development, smaller
stature, and blue sclera (Weis, Emery, Becker , n.d.). It is characterized by low bone
mass, decreased bone strength, and increased bone fragility. The clinical features
commonly include low bone mass plus reduced bone material strength, bone fragility,
susceptibility to fracture, bone deformity and growth deficiency. This mostly autosomal
dominant inheritable condition occurs in approx 1 in 15,000-20,000 births. However,
there are over 1,500 dominant mutations in either COL1A1 or COL1A2, which encode
the α-chains α1(I) and α2(I) of type I collagen (Forlino et al, 2011).
There are approximately 8 different types (I-XIII) of Osteogenic Imperfecta and
severity ranges from mild to severe with most occurring in Types I-IV, affecting all
collagen and connective body tissues. Adjunctive and supportive nutritional and dietary
therapies are necessary because symptoms of OI are lifelong and without cure. The
literature pays specific attention to severe types and conventional treatment focuses on a
multidisciplinary approach comprised of surgery, physical medicine, rehabilitation, and
the use of Bisphosphamates. There is little focus on the milder and often misdiagnosed
forms of OI that can mimick other bone, respiratory, dental, and immune conditions.
Despite the support in the literature for complimentary adjunctive medical nutrition
therapeutic approaches for similar bone and connective tissue health problems, like
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Nutritional CAM Proposal for Osteogenic Imperfecta
Osteoporosis, Osteoarthritis, Osteomalacia or Rickets, and Cystic Fibrosis; none currently
exist in the management and treatment of OI.
OI Health Issues
Regardless of the severity of Osteogenic Imperfecta, because it is a collagen deficient
condition, symptoms often affect most all body systems that involve various types of
connective tissue. As a result, a health maintenance plan for diet, lifestyle, medical care,
nutritional supplements, and rehabilitation must be life-long, optimal, and personalized.
Common health issues and complaints that affect individuals with OI are most
frequently characterized by bone fragility and Osteopenia. Based upon the type of OI,
both children and adults may experience any number of the following symptoms:
-short stature
-growth problems
-bone pain
-curvature of the spine: scoliosis and/or kyphosis
-increased dental problems
-slow and lost bone density
-weak tissues
-fragile skin
-muscle weakness
-loose joints
-bleeding problems:
-easy bruising
-frequent nosebleeds
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Nutritional CAM Proposal for Osteogenic Imperfecta
-heavy bleeding from injuries
- blood coagulation problems
- increased miscarriage rate
-pelvic work/fractures may necessitate c-section delivery
- obstetrical fracture
-hearing loss (approx. 50% childhood or early adulthood in types I and III)
- heart failure (type II)
-breathing problems (>asthma & lung problems)
-chest wall deformities leading to respiratory problems
-increased pneumonia incidence
-spinal cord or brain stem problems
-some permanent deformity and immobility
Most OI health problems an individual experiences are the result of complications
based upon the type of OI present; usually this is directly related to the problems with
weak bones & multiple fractures. Infants with OI often appear smaller and demonstrate a
slow weight gain. Some toddlers and children are short in stature and eat very little at any
one time. This can be confusing to healthcare providers as it can be mistaken for failure
to thrive.
OI Medical Workup
All types of OI are often inherited and typically require lifelong maintenance of
conditions that result from weaknesses in connective tissue throughout the body.
Families with a positive diagnosis of an OI type will need to work closely with their
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Nutritional CAM Proposal for Osteogenic Imperfecta
multi-disciplinary medical and nutrition team to address and treat symptoms and attempt
to strengthen a body system with weakened connective tissues. Because there is no cure
for OI, conventional treatment, as previously stated, has focused on surgical intervention,
physical therapy, use of the bisphosphamates. To date, there is no emphasis on special
diet or nutritional therapies for OI patients, possibly due to poorly understood nutrient
absorption and resistance as well limited nutrition specific research for OI.
However, research has positively impacted the treatment of bone and tissue disorders
related to Osteoporosis, Osteomalacia/Rickets, Osteoarthritis, and Cystic Fibrosis;
specifically when adjunctive nutritional medical regimens and CAM therapies were
utilized. This writer proposes that individuals with OI could benefit from this approach.
Several tables are provided at the back of this paper which outline specific nutrient
contributions and how they might impact OI symptoms. Additionally, a comparative
nutrient table was created where research demonstrated positive impact in the
aforementioned bone conditions. As a direct result, a nutrient-symptom table was been
created to demonstrate beneficial nutrients for treating specific OI symptoms.
In order to devise a specific health plan for the individual with mild-moderate OI, a
family medical provider (or OI healthcare specialist) will need to perform a physical
exam, diagnostic tests, blood analyses, obtain a family medical history, and take a patient
medical history. The physical examination should include an assessment that evaluates
the eyes, skin and teeth (from http://orthoinfo.aaos.org/topic.cfm).
Several diagnostics and tests may have already been performed that evaluate bone
structure, dental health, and connective tissue weaknesses. Typically X-rays will be tare
obtained to give clear images of tissues in the scull, teeth, spine, hips, hands, and feet. It
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Nutritional CAM Proposal for Osteogenic Imperfecta
is not uncommon for persons with mild OI to be “flagged” by a dentist who is able to
visually spot weaknesses in tooth architecture, enamel, dentin, and tooth pulp. Skeletal
and dental X-rays may show several small hairline fractures and bone malformations
(depending on the OI disease severity).
Specialists typically evaluate bone density in the spine and hips for persons with OI
which is more accurate than obtaining images from the hands and feet. In children and
adults with moderate to severe OI, bone densities may be performed every 6 months to 1
year to monitor bone strength and responses to medical and nutritional therapy.
Laboratory work includes blood or tissue samples that evaluate mineral content, red
blood cells structure, and genetics. Ideally, clients receive a referral for genetic testing
and counseling to help identify the specific gene mutation (this is especially important
when the parent's mutation is unknown). An OI causing mutation can be identified
through collagen biopsy or DNA analysis of the affected family member. Attempts to
collect a blood sample to perform DNA testing on the child's biological parents will help
determine if one of them is a mosaic carrier for OI. Mosaic carriers may have no
symptoms of OI but carry the mutation in a percentage of their cells.
Ultrasound is generally utilized in pregnancy to help detect any signs of OI in utero
and to follow severe cases of Osteogenic Imperfecta. Typically, health providers and
families with one affected child are understandably concerned about the possibility of
recurrence.
Genetics
Osteogenesis imperfecta (OI) constitutes a heterogeneous group of diseases that is
characterized by a susceptibility to bone fractures and collagen tissue weaknesses. This
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Nutritional CAM Proposal for Osteogenic Imperfecta
condition varies in severity and has presumed or proven defects in collagen type I
biosynthesis. The severity of OI ranges from perinatally lethal to occasional fractures
(van Dijk, Huizer, and Kariminejad, 2010).
Most patients with OI have unique collagen mutations. Approximately 300 OI-causing
mutations in type I collagen are currently recorded in the international Database of
Human Type I and Type III Collagen Mutations (Forlino et al, 2011). As with all genes
in the body, DNA is the basis for inheritance. DNA contains sections that are expressed
(exons) and sections that are not expressed (introns). DNA is translated into RNA, which
contains only those sections that are expressed. The RNA is then used to make proteins,
which are the building blocks for the human body (Basel and Steiner, 2009; Pyott, Pepin,
and Schwarze, 2011).
In approximately 90% of individuals with osteogenesis imperfecta, mutations in either
of the genes encoding the pro-α1 or pro-α2 chains of type I collagen (COL1A1 or
COL1A2) can be identified. Of those without collagen mutations, a number of them will
have mutations involving the enzyme complex responsible for posttranslational
hydroxylation of the position 3 proline residue of COL1A1 (Forlino et al, 2011). Two of
the genes encoding proteins involved in that enzyme complex, LEPRE1 and cartilage-
associated protein, when mutated have been shown to cause autosomal recessive
osteogenesis imperfecta, which has a moderate to severe clinical phenotype, often
indistinguishable from osteogenesis imperfecta types II or III. Mutations in COL1A1 or
COL1A2 which result in an abnormal protein still capable of forming a triple helix cause
a more severe phenotype than mutations that lead to decreased collagen production as a
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Nutritional CAM Proposal for Osteogenic Imperfecta
result of the dominant negative effect mediated by continuous protein turnover (Basel and
Steiner, 2009).
In most populations, recurrence of lethal osteogenesis imperfecta usually results from
parental mosaicism for dominant mutations, but the carrier frequency of recessive forms
of osteogenesis imperfecta will alter that proportion. Mutation identification is an
important tool to assess risk and facilitate prenatal or preimplantation diagnosis (Forlino
et al, 2011; Pyott, Pepin, and Schwarze, 2011).
OI occurs with equal frequency among males and females and among all racial and
ethnic groups. Approximately 35% of children with OI are born into a family with no
family history of OI. Most often this is due to a new mutation to a gene and not by
anything the parents did before or during pregnancy. A person with OI has a 50% chance
of passing on the gene and the disease to their children (van Dijk, Huizer, and
Kariminejad, 2010).
The apparent clinical variability in OI has led to the development of the classification
by Sillence et al.,initially in OI type I (mild, dominantly inherited OI with bone fragility
and blue sclerae), II (perinatal lethal), III (progressive deforming), and IV (dominant with
normal sclerae and mild deformity). Depending on the age of presentation, OI can be
difficult to distinguish from some other genetic and nongenetic causes of fractures,
including nonaccidental injury. Recently, rare autosomal recessive causes of lethal and
severe OI have been described, but in the majority of affected individuals, OI is
dominantly inherited and caused by a heterozygous mutation in either of the two genes,
COL1A1 and COL1A2, encoding the chains of type I collagen (Forlino et al, 2011). Type
I collagen is the major structural protein in bone, tendon, and ligamen. It is first
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Nutritional CAM Proposal for Osteogenic Imperfecta
synthesized in the rough endoplasmic reticulum (rER) as type I procollagen, containing
C- and N-terminal propeptides. In the rough endoplasmic reticulum, the two alpha-1
chains and the one alpha-2 chain of Gly-X-Y triplets will fold in the C-to-N direction to
form a triple helix (van Dijk, Huizer, and Kariminejad, 2010).
During folding, collagen is modified by, among others, specific enzymes that
hydroxylate lysine and proline residues and glycosylate hydroxylysyl residues. This
process is called posttranslational modification, and it stops as soon as the chain in which
the residues are located is folded.10 After folding, the procollagen molecules are
transported through the Golgi apparatus in the pericellular environment where cleavage
of the N- and C-terminal propeptides occurs and collagen molecules aggregate to form
fibrils (van Dijk, Huizer, and Kariminejad, 2010).
At present, more than 800 distinct mutations in the COL1A1 and COL1A2 genes have
been described to cause OI types II–IV. The two mildest forms of OI, OI types I and IV,
account for considerably more than half of all OI cases. OI types II–IV cases are mostly
caused by glycine substitution mutations and splice site mutations, resulting in
posttranslational overmodification and synthesis of abnormal collagen type I molecules.
In contrast, OI type I is often caused by a nonfunctional COL1A1 allele (null allele)
because of mutations generating destabilization and rapid degeneration of the mutant
COL1A1 mRNA resulting in decreased amount of normal collagen type I molecules.
Both types of abnormalities (abnormal or decreased synthesis of collagen type I) may be
detected by electrophoresis of type I collagen synthesized by cultured dermal fibroblasts.
The presence of normal collagen type I molecules explains the fact that OI type I is the
mildest type of OI. OI type I is characterized clinically by increased bone fragility often
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Nutritional CAM Proposal for Osteogenic Imperfecta
leading to fractures, ranging from few to 100,without secondary deformities in
combination with blue sclera, conductive or mixed hearing loss in late adolescence
(approximately 50% of cases), not only short but also often normal height, and
dentinogenesis imperfecta in approximately 60% of cases (Forlino et al, 2011).
Radiologically, in OI type I, bone fragility in combination with generalized
demineralization, slender shafts of tubular bones with thin cortex and poorly trabeculated
spongiosa are evident. Furthermore, ossification of the cranial vault is often retarded,
leading to a mosaic pattern of Wormian bones (van Dijk, Huizer, and Kariminejad,
2010).
Recurrence of lethal osteogenesis imperfecta in families results from either dominant
(parental mosaicism) or recessive inheritance. The proportion of these two mechanisms is
not known, and determination of the contribution of each is important to structure genetic
counseling for these families. (from www.ncbi.nlm.nih.gov/pubmed/21239989; Pyott,
Pepin, and Schwarze, 2011).
Connective tissue formation
Lysyl oxidase, a cuproenzyme, is required for the cross-linking of collagen and elastin,
which are essential for the formation of strong and flexible connective tissue. Lysyl
oxidase helps maintain the integrity of connective tissue in the heart and blood vessels
and also plays a role in bone formation (Linus Pauling Institute, 2012). RNA and DNA
can be tested to diagnose OI. The majority of OI cases are caused by a dominant mutation
to type 1 collagen (COL1A1 or COL1A2) genes. Other types are caused by mutations of
the cartilage-associated protein (CRTAP) gene or the LEPRE1 gene. This kind of