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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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

2


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

4


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

5


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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-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

7


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

8


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

9


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

10


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

12


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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http://www.ncbi.nlm.nih.gov/pubmed/21239989


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.

15


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,

16


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


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

20


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

21


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

22


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

23


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

24


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

25


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

26


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

27


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

28


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).

29


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

30


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

31


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

32


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)

33


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

34


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

35


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

36


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

37


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.

38


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

39


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).

40


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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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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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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Health & Medicine

Novel CAM Therapies in the Management of Osteogenic Imperfecta