Novel CAM Therapies in the Management of Osteogenic Imperfecta

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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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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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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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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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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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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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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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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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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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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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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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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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
mutation is inherited in a recessive manner.
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Dominant osteogenesis imperfecta is caused by defects in the quantity or structure of
type I procollagen, which affects bone at multiple levels, for example, matrix structure
and mineralization. Recessive osteogenesis imperfecta is caused by deficiency of proteins
that interact with collagen and affect its post-translational modification or folding, such
as CRTAP P3H1 and PPIB and Serpin H1 and FKBP10. Common features of dominant
and recessive osteogenesis imperfecta, for example, delayed collagen folding, effects on
bone and cartilage or increased endoplasmic reticulum stress, may be the key to
understanding its development (Forlino et al, 2011; Marini and Cabral, 2010). Mutant
procollagen chains unable to incorporate into heterotrimers are retrotranslocated into the
cytosol and degraded by the ERAD pathway; fully misfolded heterotrimers with
structural defects generate supramolecular aggregates that are eliminated by autophagy ;
mutant molecules with triple helical mutations are degraded through an unidentified
pathway (Pyott, Pepin, and Schwarze, 2011; Forlino et al, 2011). Abnormal procollagen
can be secreted, processed and incorporated in the extracellular matrix. The secreted
mutant collagen affects fibril structure and interactions of noncollagenous proteins with
matrix, as well as matrix mineralization and osteoblast development and cell-cell and
cell-matrix crosstalk. The overall result is bone deformity and fragility, although the
relative importance of various contributions is under investigation (Forlino et, 2011).
Recessive osteogenesis imperfecta with lethal to moderate phenotypes is caused by
defects in genes whose products interact with type I collagen. Most recessive cases have
null mutations in genes that encode proteins involved in collagen prolyl 3-hydroxylation
(CRTAP, LEPRE1 and PPIB) or those responsible for correct helical folding (FKBP10
and SERPINH1) (Marini and Cabral, 2010).
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Conventional Management
Clinical management of Osteogenesis Imperfecta is multidisciplinary, encompassing
substantial progress in physical rehabilitation and surgical procedures, management of
hearing, dental and pulmonary abnormalities, as well as drugs, such as bisphosphonates
and recombinant human growth hormone. Novel treatments using cell therapy or new
drug regimens hold promise for the future. (Forlino et al, 2011).
Conventional Clinical Management Team for individuals with moderate to severe OI
often include a Family Practice Health provider (MD, DO, ARNP, or PA), Orthopedic
Surgeon, Genetist, and Physical Therapist. Strong multi-disciplinary teams may also
include Dental specialists, an Audiologist, a Neurologist, an Endocrinologist, teachers,
and parents. Expanded OI health teams should also include a Complimentary Alternative
Medicine specialist, medical a Sports Medicine specialist, a Medical Nutrition Doctor, a
chiropractor, and a massage therapist.
Nonsurgical Treatment
Allopathic healthcare addresses OI using physical therapy, surgical intervention, and
sometimes medications called bisphosphonates which is designed to help slow down
bone resorption and has been shown to reduce the number of fractures and bone pain.
This medication requires close monitoring and must be administered properly by
specialists because it has multiple side effects, among them, increased bone fragility!
In other forms of non-surgical treatment for OI, extensive dental care, limb casting,
bracing, and/or splinting fractures is necessary to keep the bones still and in line so that
healing can occur. However, this also poses risks of muscle atrophy and weakeness.
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Exercise is becoming a mainstay of OI treatment because muscles and bones that
regularly exercise have greater bone mineral density and therefore greater strength;
decreasing fractures and complications. Physical therapists help design exercise that
protects bones, tendons, and ligaments; while encouraging increased bone density.
Specific exercises will increase mobility and decrease the risk of future fractures. Low-
impact exercise, such as swimming and walking, can help strengthen bones and the
muscles that support them.
Methods
This writer reviewed >95 research articles out of 126, clinical websites, and textbooks
utilizing nutritional therapies for Osteoarthritis (4), Osteoporosis (18), Osteogenic
Imperfecta (25), Osteomalacia (5), Cystic Fibrosis (1), and nutritional references to bone
and dental health (52) to serve as models for novel recommendations for adjunctive CAM
treatment in persons with mild to moderate Osteogenic Imperfecta. Publications were
obtained from scholarly works found in Pubmed, Google Scholar, and Research Journals.
Nutritional resources (2) and CAM (5) texts were reviewed for details supporting specific
actions of vitamins, minerals, and nutrient supplements that support bone, muscle, and
connective tissue growth and strengthening.
Osteogenic Imperfecta is a rare heritable connective tissue and collagen related
disorder, also known as “brittle bone disease” having varying degrees of severity
(Shriner’s, 2012). It is characterized by low bone mass, decreased bone strength, and
increased bone fragility. These individuals are susceptible to fracture, bone deformity,
and growth deficiency. They additionally they typically experience dental problems,
brittle nails, short stature, weak tissues, skin fragility, muscle weakness/pain, bone pain,
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loose joints, bleeding problems, hearing loss, and a higher rate of miscarriage (Shriners,
2012; Cluett, 2009).
Osteoporosis is characterized by fragility fractures, porous bones, reduced bone mass,
and skeletal fragility (Cashman, 2007). Bone frailty in this condition results from low
bone mass and can be related to osteopenia, a clinically significant decrease in bone mass
compared with expected values adjusted for gender and age (Lambert, 2010). Persons
with Osteoporosis experience painful, disabling spine, hip, foot, and hand fractures
related to skeletal fragility (Advani and Wimalawansa, 2003 and Love, 2003).
Osteoporosis is similar to OI due to porous bones, low bone density, and susceptibility to
fracture. Researchers believe Osteoporosis is preventable and treatable if early
interventions are implemented to reverse the cause of deficient bone health (Love, 2003).
Osteomalacia (adults) and Rickets (children) is another disorder characterized by
deficient mineral bone content (Shmerling, n.d. and Pawley & Bishop, 2004) and reduced
bone strength related to vitamin D deficiency (Pawley & Bishop, 2004). Osteoarthritis is
a degenerative joint disease caused by the breakdown of cartilage and characterized by
pain, joint damage, and limited range of motion due to stiffness (Brooks, 2011).
Although Cystic Fibrosis is a heritable respiratory disorder affecting the respiratory
passages/lungs and characterized by an oversecretion of mucous and malabsorption
syndrome, it was used because of the structural bone changes that occur in these
individuals. Increased fracture rates and kyphosis occur commonly in these individuals
due to osteoporosis related to osteopenia (Lambert, 2010).
Importance of an OI Medical Workup
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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 a
multidisciplinary 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 has focused on surgical intervention, physical therapy, use
of the bisphosphamates.
However, research is a showing positive impact in the treatment of bone and tissue
disorders related to Osteoporosis, Osteomalacia/Rickets, Osteoarthritis, and Cystic
Fibrosis when adjunctive nutritional medical regimens and CAM therapies are utilized.
This writer proposes that clients with OI could additionally benefit from this approach.
Several tables are provided at the back of this paper which outline nutrients that have had
beneficial affects in the aforementioned medical conditions. Additionally, a nutrient-
symptom table has been added to delineate which nutrients may be beneficial for treating
specific symptoms related to Osteogenic Imperfecta.
In order to create a personalized health plan for the client with mild-moderate OI, a
family medical provider or OI healthcare specialist will need to perform a thorough
exam, some diagnostic tests, take a family medical history, and client 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
structural bone, tooth, and connective tissue weaknesses. Typically X-rays will be taken
to give clear images of tissues in the scull, teeth, spine, hips, hands, and feet. It is not
18

Imperfecta
uncommon for persons with mild OI to be “flagged” by a dentist who is able to visually
spot weaknesses in tooth structure, enamel, dentin, and widening of the tooth pulp. 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 utilized in pregnancy to help detect severe cases of Osteogenic Imperfecta.
Typically, health providers and families with one affected child are concerned about the
possibility of recurrence and should be as Type II can be lethal and there is a 50% chance
of passing OI onto offspring.
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Similar Bone and Connective Tissue Diseases
Comparison Therapy Models
Extensive research exists regarding treatments for several collagen and connective
tissue diseases: Osteoporosis, Osteomalacia/Rickets, Osteoarthritis, and Cystic Fibrosis;
these conditions share similar features with OI. And they appear to demonstrate strong
evidence for nutritional supplementation positively impacting bone health. The
following sections discuss each of these bone and connective tissue conditions and
nutrient specific prescriptions and rationale.
Osteoporosis
Osteoporosis is a disease characterized by loss of bone mass, accompanied by
microarchitectural deterioration of bone tissue, which leads to an unacceptable increase in
the risk of skeletal failure/fracture (Wachman and Bernstein, 1968). Osteoporosis and
low bone mass are currently estimated to be a major public health threat. Adequate
nutrition plays a major role in the prevention and treatment of osteoporosis; the
micronutrients of greatest importance appear to be calcium and vitamin D (Cheiechi,
Secreto, D’Amore, 2002).
Risk Factors
Many genetic and lifestyle factors influence risk for osteoporosis (Cashman, 2007).
Social Habits such as deficient nutrition, lack of physical activity, smoking, and
substantial caffeine and alcohol use have been shown to decrease bone mass (Love,
2003). Bjarnason and Christiansen (n.d.) report thinness and smoking combined are
contributory to developing Osteoporosis. Although a balanced diet aids calcium
absorption, high levels of protein and sodium in the diet appear to increase calcium
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excretion through the kidneys. The popular beverages, alcohol and caffeine, categorized
as non-nutrient compounds, are found to negatively affect bone health (Illich and
Kerstetter, 2000).
Supplements
Calcium
Calcium is a critical mineral nutrient for bone health, and it is the most abundant
mineral in the human body. Because the skeleton functions as a calcium reserve, calcium
deficiency results in low bone mass, which is a major cause of osteoporosis. Many
published studies show that low calcium intake throughout life is associated with low
bone mass and high fracture rates. The NIH (2011) reports that recent studies indicate
that adequate intake of calcium reduces the risk of osteoporotic fractures, as well as other
diseases (Cashman, 2007). Several studies have shown that higher calcium intake at
various ages are associated with higher bone mineral density compared with the bone
mass of those with lower calcium intakes (Jeong and Guerinot, 2008).
The recommended calcium intake changes with age and the current recommended
intakes. The average US diet contains only 600 mg calcium a day; falling far below
recommended intakes. One of the highest daily intakes is required after age 50. The
Institute of Medicine, the recommended adequate intake for calcium is 1,000–1,300 mg/d
for adults and 1,300 mg/d for children above 9 years old. However, a significant
percentage of both children and adults consume less than the recommended amount of
calcium (Jeong and Guerinot, 2008).
Important dietary sources of non-dairy calcium are dark green vegetables; canned fish
with bones, nuts; and fortified foods. Researchers report a <500 mg twice daily calcium
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supplement is required to maximize absorption, as absorption decreases with calcium
loads >500mg and is best absorbed with food. Types of optimal calcium supplements
include: Calcium carbonate, containing >40% calcium per tablet compared to calcium
citrate which only contains 23%. The Linus Pauling Institute states that most healthy
individuals >18 years of age can safely take up to 2500 mg/day calcium (Linus Pauling
Institute, 2012).
Vitamin D
Although osteoporosis is a multifactorial disease, vitamin D insufficiency is also an
important contributing factor. The importance of vitamin D in peak bone mass is still
under investigation, however Vitamin D has demonstrated fracture benefits in
randomized clinical trials of calcium and vitamin D supplementation (Advani and
Wimalawansa, 2003). Analysis of serum 25(OH)D) can help determine adequate
calcium and vitamin D intake for optimal bone health.
Adequate nutrition plays a major role in the prevention and treatment of osteoporosis;
the nutrients of greatest importance are vitamin D and calcium (Advani and
Wimalawansa, 2003). A diet high in fruits and vegetables ensures adequate intake for
other micronutrients known to optimize bone health as they contain nutrients rich in
magnesium, potassium, vitamin C, and vitamin K. Researchers are recommending a diet
that includes 5 daily servings of fruits and vegetables to optimize micronutrients intake
required for bone health (Linus Pauling Institute, 2012).
In older postmenopausal women, the benefits of vitamin D and calcium
supplementation in preventing bone loss, decreasing bone turnover, and decreasing
nonvertebral fractures are evident. Several studies show that an inadequate intake of
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calcium, vitamin D, or both will influence calcium-regulating hormones. A deficiency of
either calcium or vitamin D will result in reduced calcium absorption and a lower
concentration of circulating ionized calcium. When this occurs, parathyroid hormone
(PTH) secretion is stimulated and there is a resulting increase in PTH levels. The
cumulative effect of higher PTH levels, secondary to poor calcium and vitamin D
nutrition (secondary hyperparathyroidism), is an increase in bone remodeling leading to
significant loss of bone and an increased fracture risk. Vitamin D supplementation, often
in combination with calcium, appears to reduce the degree of secondary
hyperparathyroidism associated with poor nutrition (Linus Pauling Institute, 2012).
In younger individuals, vitamin D synthesis in the skin is the primary determinant of
serum 25(OH)D levels; however, the cutaneous synthesis is reduced in the elderly.
Without sufficient vitamin D from sun exposure or dietary intake, intestinal calcium
absorption cannot be maximized. This causes PTH secretion by the parathyroid glands;
elevated PTH results in increased bone resorption, lead to osteoporotic fracture.
Elevations in serum PTH and greater bone loss are often associated with lower levels of
25(OH) D.
The current US recommendation for vitamin D intake in people age 51 to 70 y is 10
µg/d (400 IU/d) and over age 70 y is 15ug/d (600 IU/d. However, higher doses of vitamin
D (800–1000 IU/d) in the elderly (age ≥ 65 y) may actually be required for optimal bone
health, because these vitamin D doses have been shown to reduce fracture risk in this
population. Researchers recommend 800–1000 IU/daily compared to the current US
recommendation of 600 IU/daily vitamin D in persons >65 years of age for optimal bone
health. A prospective cohort study that followed more than 72,000 postmenopausal
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women in the U.S. for 18 years found that those who consumed at least 600 IU/day of
vitamin D from diet and supplements had a 37% lower risk of osteoporotic hip fracture
than women who consumed less than 140 IU/day of vitamin D (NIH, 2011).
The results of most clinical trials suggest that vitamin D supplementation can slow
bone density losses or decrease the risk of osteoporotic fracture in men and women who
are unlikely to be getting enough vitamin D. However, recent analyses indicate that there
is a threshold of vitamin D intake that is necessary to observe reductions in fracture risk.
For instance, a recent meta-analysis of randomized controlled trials in older adults found
that supplementation with 700 to 800 IU vitamin D daily had a 26% and 23% lower risk
of hip fracture and nonvertebral fracture, respectively. In contrast, supplementation with
400 IU of vitamin D daily did not decrease risk of either hip or nonvertebral fracture
(NIH, 2011). Additionally, recent results from the Women's Health Initiative trial in
36,282 postmenopausal women showed that daily supplementation with 400 IU of
vitamin D3, in combination with 1,000 mg calcium, did not significantly reduce risk of
hip fracture compared to a placebo. Bischoff-Ferrari et al. suggest that daily intakes of
greater than 700 IU of vitamin D may be necessary to optimize serum concentrations of
25-hydroxyvitamin D and thus reduce fracture risk (Linus Pauling Institute, 2012).
Rich sources of vitamin D include fatty fish, fish-liver oils (cod liver oil), and liver.
Several foods are also fortified with vitamin D including milk, margarine, orange juice,
and cereals. There is general agreement that the serum levels of 25(OH)D are the best
indication of adequate and inadequate vitamin D levels (Nieves, 2005).
Magnesium
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Although decreased bone mineral density (BMD) is the primary feature of
osteoporosis, other osteoporotic changes in the collagenous matrix and mineral
components of bone may result in bones that are brittle and more susceptible to fracture.
Magnesium comprises about 1% of bone mineral and is known to influence both bone
matrix and bone mineral metabolism. As the magnesium content of bone mineral
decreases, bone crystals become larger and more brittle. Some studies have found lower
magnesium content and larger bone crystals in bones of osteoporotic women compared to
non-osteoporotic controls. Inadequate serum magnesium levels are known to result in low
serum calcium levels, resistance to parathyroid hormone action, and resistance to some of
the effects of vitamin D, all of which can lead to increased bone loss (Linus Pauling
Institute, 2012).
Potassium
Potassium is an essential dietary mineral and electrolyte. At least four cross-sectional
studies have reported significant positive associations between dietary potassium intake
and bone mineral density in populations of premenopausal, perimenopausal, and
postmenopausal women as well as elderly men. The average dietary potassium intakes of
the study participants ranged from about 3,000 to 3,400 mg/day, while the highest
potassium intakes exceeded 6,000 mg/day and the lowest intakes ranged from 1,400 to
1,600 mg/day. In all of these studies, BMD was also positively and significantly
associated with fruit and vegetable intake. One study that examined changes in BMD
over time found that higher dietary potassium intakes (and fruit and vegetable intakes)
were associated with significantly less decline in BMD at the hip in men, but not in
women, over a four-year period . However, a prospective study that followed 266 elderly
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women found that women in the highest quartile of potassium excretion had higher BMD
measures after five years compared to women in the lowest quartile of potassium
excretion, suggesting that eating potassium-rich foods may help to prevent osteoporosis.
Vitamin B-6 and Vitamin C
A cofactor in the enzymatic cross-linking of collagen strands, which increases the
strength of the connective tissue, Vitamin B-6 deficient diets produced osteoporosis in
rats. Vitamin B6 helps to breakdown homocysteine, a methionine metabolite that is
believed to promote osteoporosis. Osteoporosis can also result from vitamin C
deficiency (Linus Pauling Institute 2012; NIH, 2011).
Zinc
Zinc is essential for normal bone formation as it enhances the biochemical actions of
vitamin D (NIH, 2011). Zinc levels were low in serum and bone of elderly patients with
osteoporosis. Low serum zinc levels were also found in individuals with accelerated bone
loss of the alveolar ridge of the mandible. Picolinic acid salt of zinc (zinc picolinate) a
naturally occurring metabolite of tryptophan which is believed to enhance zinc absorption
and transport in humans; appears to have a greater degree of bioavailability than other
zinc supplements (Linus Pauling Institute, 2012).
Copper Deficiency
Osteoporosis and other abnormalities of bone development related to copper
deficiency are most common in copper-deficient low-birth weight infants and young
children. Less common features of copper deficiency may include loss of pigmentation,
neurological symptoms, and impaired growth (Linus Pauling Institute, 2012).
Osteomalacia
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The free medical dictionary defines osteomalacia as a disease occurring mostly in
adult women that results from a deficiency in vitamin D or calcium and is characterized
by a softening of the bones with accompanying pain and weakness (from
http://www.thefreedictionary.com/osteomalacia). Osteomalacia and Rickets increase the
risk of fractures due to the low mineral content and reduced bone strength (Pawley &
Bishop, 2004). Deficient bone mineralization may be due to an inadequate supply of
vitamin D or it may be related to the body’s inability to regulate Vitamin D; all of which
results in significant deficiency (Shmerling, n.d.). In children this condition is called
Rickets and in adults it is referred to as Osteomalacia.
These conditions precipitate and exacerbate Osteoporosis; causing significant bone
pain, deformity, chronic inflammation and stiffness of the joints (especially those that
bear weight) and often fractures (from http://www.thefreedictionary.com/osteomalacia).
Pawley and Bishop (2004) implicate poor vitamin D supplementation in infancy leads to
biochemical disturbances, reduced bone mineralization, slower growth, and alterations in
bone shape; increasing fracture risk. Although adult bones are no longer growing, they
exist in a constant state of turnover and remodeling. For persons with severe vitamin D
deficiency, the collagenous bone matrix is preserved but bone mineral is progressively
lost, resulting in bone pain due to soft bones and known as Osteomalacia (Linus Pauling
Institute, 2012; NIH, 2011).
Adequate vitamin D is essential for proper bone growth and development in children.
Pediatricians maintain that a higher daily dose of vitamin D will not only prevent but also
treat rickets (Fryhofer, 2012). Obese children and adults on anticonvulsant medications,
glucocorticoids, antifungals, and AIDS medications require 2-3 times more vitamin D
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than their age group to satisfy their body’s vitamin D requirement (Lambert, 2010).
Children with Vitamin D deficiency aged 1-18 years, should be treated with 2000 iu/daily
with D2 or D3 6 weeks, or 50,000 iu per week of Vitamin D2 or D3 for 6 weeks to
achieve blood levels of 25(OH)D above 30ng/mL, followed by maintenance of 600-1000
iu/d. Adults aged 19-70 years require at least 600IU/day of vitamin D to maximize bone
health and muscle function. However, getting 25(OH)D levels consistently above
30ng/mL may require at least 1500-2000 IU of vitamin D (Brooks, 2011).
Arthritis
Osteoarthritis is known as degenerative joint disease and caused by the breakdown of
cartilage (Brooks, 2011). Typically it is characterized by pain, joint damage, and limited
range of motion (from http://nccam.nih.gov/health/arthritis). Research is ongoing in the
search to find adequate treatments to halt the progress of osteoarthritis, restore health, and
reduce pain to improve quality of life in these individuals. There remains limited
information and research in these areas related to this condition. However, promising
research is emerging. Among them, was a Two-Year GAIT Study performed in 2010 that
produced new data from a long-term study of the dietary supplements on glucosamine
and chondroitin for knee osteoarthritis pain. The results were encouraging as they
revealed that patients who took the supplements (alone or in combination) had outcomes
similar to those experienced by patients who took celecoxib or placebo pills
( http://nccam.nih.gov/health/glucosamine).
NIH reports Omega-3 fatty acids have been found to reduce pain and swelling (from
http://www.nlm.nih.gov/medlineplus/druginfo/natural/993.html). Additionally, fish oil
alone, or in combination with the drug naproxen seems to help people with rheumatoid
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arthritis get over morning stiffness faster. People who take fish oil have demonstrated
reduced dose and use of non-steroidal anti-inflammatory pain meds. Patients with
rheumatoid arthritis found relief taking Fish oil doses of 3.8 grams/day of EPA and 2
grams/day DHA (from http://www.nlm.nih.gov/medlineplus/druginfo /natural/993.html).
PABA is also cited as helping to reduce arthritis inflammation (Balch, 2002).
Some individuals with osteoarthritis have found using the product Phlogenzym, which
combines bromelain with trypsin (a protein) and rutin (a substance found in buckwheat),
was helpful in reducing arthritic pain and inflammation and improved knee function
(from http://www.nlm.nih.gov/medlineplus /druginfo/natural/895.html).
Cystic Fibrosis
Cystic fibrosis is a hereditary disease of the exocrine glands, usually developing
during early childhood and affecting mainly the pancreas, respiratory system, and sweat
glands. It is characterized by the production of abnormally viscous mucus by the affected
glands, usually resulting in chronic respiratory infections and impaired pancreatic
function (from http://www.thefreedictionary.com/cystic+fibrosis).
Bone changes, increased fracture rates, and kyphosis in Cystic Fibrosis are
consequences of Osteoporosis. Here, bone frailty results from low bone mass and may be
secondary to Osteopenia, a clinically significant decrease in bone mass compared with
expected values adjusted for gender and age. Among factors thought to be involved in the
pathologic process in these patients are low weight and short stature, disease severity:
nutrition status and pulmonary function, chronic inflammation, low levels of physical
activity, poor calcium and vitamin D absorption, corticosteroid therapy, and
hypogonadism (Aris, n.d. and Lambert, 2010).
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Chronic inflammation due to the pulmonary condition in CF induces sustained
production of TNF-a, a mediator linked to cachexia and weight loss, significant
inhibition of collagen production, and increased IL-6 production by stromal and
osteoblastic precursor cells. Therefore, inflammatory mediators may be partly responsible
for the pathogenesis of osteopenia and osteoporosis in CF. It is speculated that disease
severity and chronic inflammation could be important causes of impaired bone
mineralization in juvenile rheumatoid arthritis (Aris, n.d.).
Diet and Nutrients
Calcium absorption in the intestine may be lower in AWCF and bone calcium
deposition is lower in CF children. Thus, reduction in the rate of bone calcium deposition
in the bones may contribute to reduced bone mass (Aris, n.d.). More than 20 reports
found vitamin D insufficiency common in CF. Food rich in Vitamin D and Calcium
should be present in the daily diet.
Lifestyle Habits and Nutrient-Poor Foods
Caffeine increases urinary calcium, and therefore should be consumed in small
quantities by patients with CF. Some soft drinks contain large concentrations of
phosphorus, which binds calcium in the intestine, so excessive daily consumption of
these drinks should be avoided. Smoking and alcohol use have been linked to lower bone
mass and increased fracture rates (Lambert, 2010).
Exercise
A positive correlation was seen between time spent in weight-bearing activity and
lumbar spine BMAD, and a trend toward significance for BMD was observed for BMD z
scores. Bones should be mechanically loaded to prevent density reductions, and tolerable
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exercise along with avoidance of complete bed rest. Weight loss associated with
physical activity in subjects who are initially underweight is not desirable. Anyone with
osteoporosis who begins an exercise program needs to receive adequate intakes of
proteins, vitamins and minerals.
Discussion
Assessing the literature and texts on bone health and repair, therapeutic nutritional
supplement practices used in the treatment of Osteoporosis, Osteoarthritis, Fracture care,
Osteomalacia and Rickets, and Cystic Fibrosis bone problems helped to guide my
research to uncover possible nutritional therapies in the treatment and management of
mild to moderate forms of Osteogenic Imperfecta and propose nutritional therapies for OI
symptoms (see Table 4).
Much of the research on nutritional medicine and bone health has occurred within this
last decade and only address Osteoporosis, Osteomalacia/Rickets, and Cystic Fibrosis
bone and connective tissue problems. Much needs to be learned about Osteogenic
Imperfecta because deficits in body collagen and connective tissues vary from person to
person and are multifactorial. Nutrients have to be carefully balanced with each person
and depending upon the individual’s OI severity, growth and development, pregnancy
state, comorbid health problems, and gender; causing variations and adjustment in
nutrient therapies for OI.
OI is often misdiagnosed because it shares similar features with many bone,
connective tissue, dental, skin, respiratory, and autoimmune illnesses. Very few OI
specialists exist in the community and many of them do not have an adequate nutritional
medicine background to make appropriate nutritional or Complimentary Alternative
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Medicine recommendations to their OI patients. Future education in the recognition and
treatment of the milder forms of OI for family practice providers would beneficial in
accessing early care and CAM therapies. Adjunctive CAM therapies may not cure OI,
but they could greatly reduce the complications and discomfort individuals experience.
Other issues that were not addressed in this paper include cost of nutritional
supplements and whole foods diet, impact upon family dynamics, depression and body
image, and caregiver and client OI resources. Results and Recommendations
There is no known cure for Osteogenic Imperfecta and currently conventional
therapies only focus on surgical intervention, dental care, physical therapy, protection,
and the use of bisphosphamates. Although much attention has been given to the use of
bisphosphamates in children and adolescents to build bone density, it has serious
drawbacks due to the narrow therapeutic window. It has been shown that despite bone
building properties in Bisphosphamates, they also have been shown cause bone
resorption and weakening in persons as well.
Mild to moderate forms of Osteogenic Imperfecta are typically underdiagnosed,
misdiagnosed, or receive delayed diagnosis. Researchers understand that OI presents with
many symptoms that mimic other medical conditions and childhood growth and
development complaints.
Research has demonstrated and is emphasized in other medical conditions that
nutrition and nutrient supplementation can have a positive impact on strengthening
weakened body structures and immune systems. This is being positively demonstrated in
the use of vitamin A in linear growth curves in undernourished Pakistani children, the
reduction of stress fractures with the use of Vitamin D in athletic teen girls, the use of
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supplemental vitamin D in persons with Osteomalacia/Rickets, the use of supplemental
calcium and vitamin D in persons with Osteoporosis, and the use of Vitamin C in treating
scurvy.
Research in the literature is lacking related to medical nutritional interventions and
adjunctive CAM therapies. Much of the focus on the treatment of Osteogenesis
Imperfecta has been fracture prevention and treatment. There are no specific dietary or
nutritional intervention studies found in the literature. Currently, research does not exist
on persons with any specific type of OI regarding the affects of supplemental Calcium,
vitamin D, magnesium, or other nutrients. The research focus remains strictly
pharmacological.
The literature shows promise that specific nutrients could contribute to strengthening
weak bone and tooth structures with the implimentation of specific dietary and nutritional
interventions in persons with OI. Because OI shares similar features with Osteoporosis,
Osteomalacia/Rickets, and the structural changes that occur in bones in persons with
Cystic Fibrosis; possible adjunctive CAM treatment models could be proposed for OI
based upon research that has been performed on the aforementioned conditions and
nutritional medicine therapies that have been designed as a result.
Model Conclusions for OI
Nutrients
The Institute of Medicine, the recommended adequate intake for calcium is 1,000–
1,300 mg/d for adults and 1,300 mg/d for children above 9 years old. Other researchers
recognize that calcium supplements, even in dosages of 800 – 1,500 mg/day, play an
important role in prevention and treatment of bone loss (Gaby and Wright, 2012)
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Researchers recommend 800–1000 IU/daily compared to the current US
recommendation of 600 IU/daily vitamin D in persons >65 years of age for optimal bone
health. Vitamin D supplementation, often in combination with calcium, appears to
reduce the degree of secondary hyperparathyroidism associated with poor nutrition
(Linus Pauling Institute, 2012). Higher doses of vitamin D (800–1000 IU/d) (age ≥ 65 y)
in Vitamin D deficient individuals are required for optimal bone health, because these
vitamin D doses have been shown to reduce fracture risk in this population. The Institute
of Medicine recommends no more than 4,000 IU per day of D3 for adults (NIH, 2011).
Additionally, without sufficient vitamin D2 from sun exposure or dietary intake,
intestinal calcium absorption cannot be maximized.
Vitamin D should be supplemented in cases where dietary intake and sunlight
exposure are inadequate. Measures should also be taken to enhance the conversion of
vitamin D precursors to the biologically active 1,25-dihydroxyvitamin D3. This
conversion may be facilitated by treatment with magnesium and boron because a
deficiency of magnesium can produce a syndrome of "vitamin D resistance" (NIH, 2011).
Obese children and adults on anticonvulsant medications, glucocorticoids, antifungals,
and AIDS medications will require 2-3 times more vitamin D than their age group to
satisfy their body’s vitamin D requirement (Lambert, 2010). Children with Vitamin D
deficiency aged 1-18 years, should be treated with 2000 iu/daily with D2 or D3 6 weeks,
or 50,000 iu per week of Vitamin D2 or D3 for 6 weeks to achieve blood levels of
25(OH)D above 30ng/mL, followed by maintenance of 600-1000 iu/d. Adults aged 19-
70 years require at least 600IU/day of vitamin D to maximize bone health and muscle
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function. Successfully elevating the 25(OH)D levels consistently above 30ng/mL may
require at least 1500-2000 IU of vitamin D (Brooks, 2011).
Glucosamine and chondroitin may be helpful in managing bone pain related to OI as
evidenced by results in the Two-Year GAIT Study on the supplements taken alone and in
combination, had outcomes similar pain relief outcomes compared to those experienced
by patients who took celecoxib or placebo pills
( http://nccam.nih.gov/health/glucosamine).
Dietary Nutrients and Supplements
A whole foods unrefined diet is essential for optimal bone health in individuals with
OI due to their clinical makeup. It is essential that non-nutritive food sources be
eliminated from their diet to maximize their bone and connective tissue strength and
reduce other symptoms of pain, bruising, and dental problems. Avoidance of refined flour
and use of whole grains are important for collagen and connective tissue health.
A diet high in fruits and vegetables ensures adequate intake for other micronutrients
known to optimize bone health as they contain nutrients rich in magnesium, potassium,
vitamin C, and vitamin K. Researchers are recommending a diet that includes 5 daily
servings of fruits and vegetables to optimize micronutrients intake required for bone
health (Linus Pauling Institute, 2012). Deficiency may occur in individuals whose
vegetable consumption is low (NIH, 2011).
The therapeutic OI diet must also be rich in vitamin B-6, vitamin C, and copper to
increase the strength of connective tissue. Include a potassium-rich diet to prevent
osteoporosis by ingesting approximately 3,000 to 3,400 mg/day of dietary potassium.
Because bone dissolution is considered a possible mechanism to buffer the fixed acid
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load imposed by the ingestion of an "acid ash" diet (Wachman & Bernstein, 1968),
therefore, ingesting an 80/20 Alkaline/Acid whole foods diet is recommended. Chiechi et
al indicate that consuming soy products can be potentially effective in reducing the risk
of bone fragility (2002). It is now recognized that a balanced diet aids in calcium
absorption, but high levels of protein and sodium are found to increase calcium excretion
through the kidneys. Excessive amounts of these substances need to be avoided,
especially in those with low calcium intake (NIH, 2011).
Water
Persons with Osteogenic Imperfecta must obtain enough water in their diet and avoid
an excess of foods and beverages that would cause depletion. Researchers now
understand that water is necessary for life; participating in all body cellular and metabolic
processes, and is vital in the elimination of body toxins. Water is known to help relieve
headaches, anxiety, muscle pains, and extreme fatigue. It is essential for breathing
because it helps facilitate oxygen intake and CO2 exchange. Water is functions to
lubricate body joints, improve arthritis, glaucoma, cataracts, diabetesand hypoglycemia
as well as slow the aging process (Barimeus, 2009).
Calcium
Dietary sources of non-dairy calcium are dark green vegetables; canned fish with
bones, nuts; and fortified foods. Researchers report a <500 mg twice daily calcium
supplement is required to maximize absorption, as absorption decreases with calcium
loads >500mg and is best absorbed with food. Types of optimal calcium supplements
include: Calcium carbonate (contains 40% >calcium per tablet) compared to calcium
citrate (contains 23%). In most healthy individuals >18 years of age, calcium intakes up
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to 2500 mg/d are considered safe (Linus Pauling Institute, 2012). However, the
percentage of calcium absorbed depends on the total amount of elemental calcium
consumed at one time; as the amount increases, the percentage absorption decreases.
Absorption is highest in doses ≤500 mg. Therefore, an individual with OI should divide
1,000 mg/day of calcium into 500 mg twice daily doses (retrieved from
http://ods.od.nih.gov/factsheets/calcium-HealthProfessional/).
Vitamin D
Rich sources of vitamin D include fatty fish, fish-liver oils (ie. cod liver oil), and liver
(NIH, 2011). Several foods are also fortified with vitamin D including milk, margarine,
orange juice, and cereals. There is general agreement that the serum levels of 25(OH)D
are the best indication of adequate and inadequate vitamin D levels (Nieves, 2005).
Taking fish oil alone or in combination with calcium and evening primrose oil seems to
slow bone loss rate and increase bone density at the thigh bone and spine in elderly
people with osteoporosis (from http://www.nlm.nih.gov/medlineplus/druginfo
/natural/993.html). The NIH encourages taking Omega-3 fatty acids because they have
been found to reduce pain and swelling. Fish oil providing 3.8 grams/day of EPA and 2
grams/day DHA may be helpful for persons with OI experiencing similar symptoms.
Vitamin C
Ascorbic acid (vitamin C) is a cofactor required for the function of several
hydroxylases and monooxygenases. It is not synthesized in humans and some other
animal species and has to be provided by diet or pharmacologic means. Its absence is
responsible for scurvy, a condition related in its initial phases to a defective synthesis of
collagen. Vitamin C is especially necessary for persons with OI to assist with tissue
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growth and repair, collagen formation, and prevention of abnormal blood clotting and
bruising Additionally, it improves immune system protein, is needed for folic acid,
tyrosine, phenylalanine metabolism, and helps reduce asthma symptoms, and protects
against infection and enhances immunity (Balch, 2002).
Other Nutrients
Other necessary whole food dietary components required for normal bone metabolism
include protein, magnesium, manganese, zinc, copper, iron, fluoride, vitamins D, A, C,
and K are (Gaby and Wright, 2012). High-dose vitamin A supplementation improves the
linear growth of children with very low serum retinol and the effect is modified by age
and breast-feeding. Many cross-sectional studies have linked vitamin A deficiency to a
greater risk of being stunted (Hadi, Stoltzfus, Dibley, Moulton, West, Kjolhede and
Sadjimin, 2000). Vitamin K is considered essential for bone formation, remodeling, and
repair.
Folic acid is essential for bone health related to its role in homocysteine metabolism.
Methionine, one of the eight essential amino acids present in food, is converted in part to
homocysteine. Researchers believe that individuals who develop severe osteoporosis
early, is the direct result of homocysteine’s adverse effects on bone; Folic acid keeps
homocysteine levels low (NIH, 2011). Manganese is required for bone mineralization,
and for synthesis of connective tissue in cartilage and bone. Investigators report that half
of the manganese in a typical diet is lost when whole grains are replaced by refined
flour(NIH, 2011).
Zinc is essential for normal bone formation as it enhances the biochemical actions of
vitamin D. Zinc levels were low in serum and bone of elderly patients with osteoporosis.
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Low serum zinc levels were also found in individuals with accelerated bone loss of the
alveolar ridge of the mandible. Zinc picolinate appears to have a greater degree of
bioavailability than other zinc supplements. Picolinate is a naturally occurring metabolite
of tryptophan which is believed to enhance zinc absorption and transport in humans
(Linus Pauling Institute, 2012).
Exercise
Weight-bearing physical activities cause muscles and bones to work against gravity.
For bone health, adults should engage in >30 minutes of moderate physical activity most,
days of the week. Children need to engage in >60 minutes of moderate physical activity
daily (CDC, 2012). A positive correlation was seen between time spent in weight-
bearing activity and lumbar spine BMAD, and a trend toward significance for BMD
(although with a weak correlation) was observed for BMD z scores (Lambert, 2010).
Non-Nutrient Foods
Excessive amounts of caffeine and alcohol should be avoided, especially those with
low calcium intake, because they cause bone fragility by blocking nutrient uptake and
increasing nutrient excretion (Ilich & Kerstetter, 2000). Caffeine increases urinary
calcium, and therefore should be consumed in small quantities by patients with OI. Many
soft drinks contain large concentrations of phosphorus, which binds calcium in the
intestine, so excessive daily consumption of these drinks should be avoided (Lambert,
2010).
Botanicals
Turmeric, an herb commonly used in curry powders, mustards, and cheese, may
protect bones against osteoporosis, according to a recent laboratory study published in the
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Journal of Agricultural and Food Chemistry (http://nccam.nih.gov/research/results/
spotlight/093010.htm).
Bromelain is used for reducing swelling (inflammation), especially of the nose and
sinuses, after surgery or injury. It is also used for hay fever, treating a bowel condition
that includes swelling and ulcers (ulcerative colitis), removing dead and damaged tissue
after a burn (debridement), preventing the collection of water in the lung (pulmonary
edema), relaxing muscles, stimulating muscle contractions, slowing clotting, improving
the absorption of antibiotics, preventing cancer, shortening labor, and helping the body
get rid of fat (from http://www.nlm.nih.gov/medlineplus/druginfo/natural/895.html), this
particular nutrient may be helpful in alleviating some of these same symptoms in persons
with OI.
Evening primrose oil has linoleic acid and gamma-linolenic acid (“GLA”) thought to
reduce swelling or irritation typically it is taken in divided doses of 360mg-2.8g daily.
NIH recommends always taking this along with some form of antioxidant, like vitamin E,
to ensure that the unsaturated fatty acids don’t oxidize (from http://nccam.nih.gov
/health/eveningprimrose)
Other Cautions
Frequent use of antibiotics appears to promote vitamin deficiency leading to bone
resorption (NIH, 2011). In persons with OI, care should be taken to use nutrients that
build immunity and strengthen respiratory health to lessen the use of antibiotics.
Tobacco smoking, drinking alcohol, and using oral contraceptives also tend to
promote folic acid deficiency. Smoking and alcohol use have been linked to lower bone
mass and increased fracture rates (Lambert, 2010).
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Pregnancy and Fetal Development
Vitamin D levels should be monitored routinely for pregnant persons with OI to
maximize health of both the mother and fetus as bone mineral resorption is highest for in
pregnancy. Maternal vitamin D insufficiency during pregnancy is associated with a
number of adverse health outcomes in offspring, including poor fetal growth, weaker
bones, and asthma during childhood (Brooks, 2011). Vitamin D is important for fetal
development (Fryhofer, 2012). Ingestion of fish oil 4 grams daily, providing 32% EPA
and 23% DHA with tocopherol, during late-phase pregnancy has been used for
preventing the development of asthma in children (http://www.nlm.nih.gov/medline
plus/druginfo/natural/993.html) and may be beneficial in persons with known OI.
Pregnant women with OI should avoid caffeine, salt, carbonated beverages, and diets
high in refined flours and sugars. Metabolic acids produced by diets high in protein and
cereal grains increase calcium excretion. Fruits and vegetables, when metabolized, shift
the acid/base balance of the body towards the alkaline by producing bicarbonate, which
reduces calcium excretion (from http://ods.od.nih.gov/factsheets/calcium-
HealthProfessional/).
Additionally, pregnancy necessitates the need for a whole foods diet high in fresh
water and nutrients and the avoidance of nutrient poor beverages, snacks, and processed
foods. Diets high in cereal grains and proteins should be avoided because they increase
calcium excretion (NIH, 2011). Social habits such as deficient nutrition, lack of physical
activity, smoking, and substantial caffeine and alcohol decrease bone mass (Lambert,
2000).
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Imperfecta
Persons with OI need to be seen by a specialist who understands their unique health
needs. There is an increased risk of bleeding problems, lower nutrient absorption,
miscarriage, pain, and fetal injury in women with OI. Working with an OB-gyn
specialist, an orthopedist, a nutritional medicine specialist, and a massage therapist can be
essential for a safe delivery and healthy baby. Supplements will be needed and an
experienced Nutrition Medicine Doctor can help the individual with OI determine what
her specific nutrient needs are during pregnancy and lactation.
Myalgias
Vitamin B complex, including 30-mg vitamin B6, has also shown effectiveness (Hadi
et al, 2000). Muscle pain and weakness can also be caused by vitamin D deficiency.
Some experts anecdotally report that repleting vitamin D can help manage statin-induced
myalgias (Fryhofer, 2012).
Literature Contradictions
Controversy exists regarding which foods can adequately supply enough bioavailable
calcium to the body. Some experts believe dairy foods are the best sources of calcium,
believing the amount of bioavailable calcium in fruits and vegetables too low, however,
other experts maintain that dairy foods prevent proper absorption in the gut due to the
pasteurization process. Researchers Jeong and Guerinot (2008) report that although
many vegetables contain high levels of calcium, plants also have oxalic acid and phytate,
which inhibit calcium absorption. They stress that increased levels of nutrients are not
necessarily correlated with enhanced bioavailability. In fact, the calcium absorption
efficiency from sCAX1-expressing carrots was lower than that from control carrots,
probably because not all of the extra calcium in the vacuole was bioavailable due to the
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Imperfecta
antinutrients within the carrots. Still other experts focus on non-dairy foods such as
salmon, broccoli, and seeds maintaining they are ideal sources of high levels of
bioavailabe calcium.
Future Research
Nutritional and dietary interventions for OI need to be designed to first, alleviate the
symptoms of soft teeth, soft bone structure, muscular pain, arthralgias, and the like.
Proposed nutrients for investigation would include Calcium, Vitamin C, Vitamin D,
Vitamin E, Magnesium, Copper, and Omega 3 and 6 Fatty Acids. Analysis of diet,
symptoms, and growth could be performed safely on infants through young adults.
Additionally, massage, yoga, low impact strength training could be utilized and assessed.
Future studies need to involve persons with varying degrees of Osteogenic Imperfecta
who can participate in dietary, supplement, and low impact weight bearing exercise
interventions. Analysis could be performed using Dexascans of their hips and spine,
standard pain assessment forms, blood studies, and Activities of Daily Living to assess
the impact that these therapy interventions have on the patient’s health and quality of life.
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Imperfecta
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Novel CAM Therapies in the Management of Osteogenic Imperfecta

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