Cannabinoids as adjunct treatment for symptoms of OI

OSTEOGENESIS IMPERFECTA

Osteogenesis imperfecta is a condition causing extremely fragile bones.
Osteogenesis imperfecta (OI) is a congenital disease, meaning it is present at birth.  It is frequently caused by defect in the gene that produces type 1 collagen, an important building block of bone. There are many different defects that can affect this gene.  The severity of OI depends on the specific gene defect.
OI is an autosomal dominant disease.  That means if you have one copy of the gene, you will have the disease.  Most cases of OI are inherited from a parent, although some cases  are the result of new genetic mutations.
A person with OI has a fifty percent chance of passing on the gene and the disease to their children.

Types

There are eight different types of OI, Type I being the most common, though the symptoms vary from person to person.

Type I

1. Blue sclera in osteogenesis imperfecta. 
2. Collagen is of normal quality but is produced in insufficient quantities:
3. Bones fracture easily
4. Slight spinal curvature
5. Loose joints
6. Poor muscle tone

Discoloration of the sclera (whites of the eyes), usually giving them a blue-gray color. he blue-gray color of the sclera is due to the underlying choroidal veins which show through.    This is due to the sclera being thinner than normal because of the defective Type I collagen not forming correctly.

7   Early loss of hearing in some children
8   Slight protrusion of the eyes

IA and IB are defined by the absence/presence of dentinogenesis imperfecta (characterized by opalescent teeth;  absent in IA, present in IB).  Life expectancy is slightly reduced compared to the general population due to the possibility of fatal bone fractures  and complications related to OI Type I.

Type II

Collagen is not of a sufficient quality or quantity.  Most cases die within the first year of life due to respiratory failure or intracerebral hemorrhage.  Severe respiratory problems due to underdeveloped lungs.  Severe bone deformity and small stature.  Type II can be further subclassified into groups A, B, C, which are distinguished by radiographic evaluation of the long bones and ribs.  Type IIA  demonstrates broad and short long bones with broad and beaded ribs.  Type IIB  demonstrates broad and short long bones with thin ribs that have little or no beading.  Type IIC demonstrates thin and longer long bones with thin and beaded ribs.

Type III

1. Collagen improperly formed.  Enough collagen is made but it is defective
2. Bones fracture easily, sometimes even before birth
3. Bone deformity, often severe
4. Respiratory problems possible
5. Short stature, spinal curvature and sometimes barrel-shaped rib cage
6. Triangular face
7. Loose joints
8. Poor muscle tone in arms and legs
9. Discolouration of the sclera (the 'whites' of the eyes), often turning blue during severe -break.
10. Early loss of hearing possible

Type III  is distinguished among the other classifications as being the "Progressive Deforming" type, wherein a neonate presents with mild symptoms at birth and develops  the aforementioned symptoms throughout life.  Lifespan may be normal, albeit with severe physical handicapping.

Type IV

1. Collagen quantity is sufficient but is not of a high enough quality
2. Bones fracture easily, especially before puberty
3. Short stature, spinal curvature and barrel-shaped rib cage
4. Bone deformity is mild to moderate
5. Early loss of hearing

Similar to Type I,  Type IV can be further subclassified into types IVA and IVB characterized by absence (IVA) or presence (IVB) of dentinogenesis imperfecta.

Type V

Same clinical features as Type IV.  Distinguished histologically by "mesh-like" bone appearance.  Further characterized by the "V Triad" consisting of  a) radio-opaque band adjacent to growth plates, b) hypertrophic calluses at fracture sites, and c) calcification of the radio-ulnar interosseous membrane.
OI Type V leads to calcification of the membrane between the two forearm bones, making it difficult to turn the wrist.  Another symptom is abnormally large amounts of repair tissue (hyperplasic callus) at the site of fractures.  At the present time, the cause for Type V  is unknown, though doctors have determined that it is inherited.

Type VI

Same clinical features as Type IV. Distinguished histologically by "fish-scale" bone appearance.

Type VII

In 2005 a recessive form called "Type VII" was discovered (Phenotype severe to lethal).  Thus far it seems to be limited to a First Nations people in Quebec.
Mutations in the gene CRTAP causes this type.

Type VIII

OI caused by mutation in the gene LEPRE1 is classified as type VIII.

Symptoms:

All people with OI have weak bones, which makes them susceptible to fractures.  Persons with OI are usually below average height ( short stature).  However, the severity of the disease varies greatly.
The classic symptoms include:

• Blue tint to the whites of their eyes (blue sclera)
• Multiple bone fractures
• Early hearing loss (deafness)
• Because type I collagen is also found in ligaments, persons with OI often have loose joints (hypermobility) and flat feet.  Some types of OI also lead to the development of poor teeth.
• Symptoms of more severe forms of OI may include:
• Bowed legs and arms
• Kyphosis
• Scoliosis (S-curve spine)

Treatment:

There is not yet a cure for this disease. However, specific therapies can reduce the pain and complications associated with OI.
Bisphosphonates are drugs that have been used to treat osteoporosis.  They have proven to be very valuable in the treatment of OI symptoms, particularly in children. These drugs can increase the strength and density of bone in persons with OI.
Bisphosphonates (BPs), particularly those containing nitrogen, are being increasingly administered to increase bone mass and reduce the incidence of fracture.  BPs can be dosed orally (e.g. alendronate) or by intravenous injection/infusion (e.g. pamidronate, zoledronic acid).
BP therapy is being used increasingly for the treatment of OI. I t has proven efficiency in reducing fracture rates in children, however only a trend towards decreased fracture was seen in a small randomized study in adults.  While decreasing fracture rates, there is some concern that prolonged BP treatment may delay the healing of OI fractures, although this has not been conclusively demonstrated.

Pamidronate is used in USA, UK and Canada.  Some hospitals, such as most Shriners, provide it to children. Some children are under a study of pamidronate.  Marketed under the brand name Aredia, Pamidronate is usually administered as an intravenous infusion, lasting about three hours.  The therapy is repeated every three to six months, and lasts for the life of the patient.  Common side effects include bone pain, low calcium levels, nausea, and dizziness.  According to recent results, extended periods of pamidrinate, (6 years) can actually weaken bones, so patients are recommended to get bone densities every 6 months to one year,  to monitor bone strength.

Treatment and Surgery

Metal rods can be surgically inserted in the long bones to improve strength, a procedure developed by Harold A. Sofield, MD, at Shriners Hospitals for Children in Chicago.  During the late 1940s, Sofield, Chief of Staff at Shriners Hospitals in Chicago, worked there with large numbers of children with OI and experimented with various methods to strengthen the bones in these children.    In 1959, with Edward A. Miller, MD, Sofield wrote an  article describing a solution that seemed radical at the time:  the placement of stainless steel rods into the intramedullary canals of  the long bones to stabilize and strengthen them.  His treatment proved extremely useful in the rehabilitation and prevention of fractures;  it was adopted throughout the world and still forms the basis for orthopedic treatment of OI.
Spinal fusion can be performed to correct scoliosis, although the inherent bone fragility makes this operation more complex in OI patients.  Surgery for basilar impressions can be carried out if pressure being exerted on the spinal cord and brain stem is causing neurological problems.

Exercise  can greatly reduce bone pain and fracture rate (especially in the bones of the spine).
Low impact exercises such as swimming keep muscles strong and help maintain strong bones.  Such exercise can be very beneficial for persons with OI and should be encouraged.
In more severe cases, surgery to place metal rods into the long bones of the legs may be considered to strength the bone and reduce the risk of fracture.  Bracing can also be helpful for some people.

Reconstructive surgery may be needed to correct any deformities.  Such treatment is important because deformities (such as bowed legs or a spinal problem) can significantly affect a person's ability to move or walk.
Regardless of treatment,  fractures will occur.  Most fractures heal quickly.  Time in a cast should be limited since bone loss (disuse osteoporosis) may occur when you do not use a part of your body for a period of time.
Many children with OI develop body image problems as they enter their teenage years.  A social worker or psychologist can help them adapt to life with OI.

Complications

Complications are largely based on the type of OI present.  They are often directly related to the problems with weak bones and multiple fractures.
Complications may include:

• Hearing loss (common in type I and type III)
• Heart failure (type II)
• Respiratory problems and pneumonias due to chest wall deformities
• Spinal cord or brain stem problems
• Permanent deformity

Physiotherapy

Physiotherapy  used to strengthen muscles and improve motility in a gentle manner, while minimizing the risk of fracture.  This often involves hydrotherapy and the use of support cushions to improve posture. Individuals are encouraged to change positions regularly throughout the day in order to balance the muscles which are being used and the bones which are under pressure.
Children often develop a fear of trying new ways of moving due to movement being associated with pain. This can make physiotherapy difficult to administer to young children.

Physical aids

With adaptive equipment such as crutches, wheelchairs, splints, grabbing arms, and/or modifications to the home many individuals with OI can obtain a significant degree of autonomy.

Prevention

Genetic counseling is recommended for couples considering pregnancy if there is a personal or family history of this condition.

Expectations

How well a person does depends on the type of OI they have.
Type I, or mild OI, is the most common form.  Persons with this type can live a normal lifespan.
Type II is a severe form that is usually leads to death in the first year of life.
Type III is also called severe OI.  Persons with this type have many fractures starting very early in life and can have severe bone deformities.  Many become wheelchair bound and usually have a somewhat shortened life expectancy.

Type IV, or moderately severe OI, is similar to type I, although persons with type IV often need braces or crutches to walk.  Life expectancy is normal or near normal.
There are other types of OI, but they occur very infrequently and most are considered subtypes of the moderately severe form (type IV).

History

The condition, or types of it, have had various other names over the years and in different nations.  Among some of the most common alternatives are Ekman-Lobstein syndrome, Vrolik syndrome, and the colloquial glass-bone disease.  The name osteogenesis imperfecta dates to at least  1895  and has been the usual medical term in the 20th century to present.  The current four type system began with Sillence in 1979.  An older system deemed less severe types "osteogenesis imperfecta tarda" while more severe forms were deemed "osteogenesis imperfecta congenita."   As this did not differentiate well, and all forms are congenital, this has since fallen out of favour.
The condition has been found in an Ancient Egyptian mummy from 1000 BC.  The Norse king Ivar the Boneless may have had this condition as well.  The earliest studies of it began in 1788 with the Swede Olof Jakob Ekman.  He described the condition in his doctoral thesis and mentioned cases of it going back to 1678.

Epidemiology

In the United States, the incidence of osteogenesis imperfecta is estimated to be one per 20,000 live births.
Frequency is approximately the same across groups, but for unknown reasons the Shona and Ndebele of Zimbabwe  seem to have a higher proportion of Type III to Type I  than other groups.  However,  a similar pattern was found in segments of the Nigerian and South African population. 

Cannabinoid Research

CANNABINOIDS AND BONE: ENDOCANNABINOIDS MODULATE HUMAN OSTEOCLAST FUNCTION IN VITRO.
L S Whyte, L Ford, S A Ridge, G A Cameron, M J Rogers, R A Ross
Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen. Scotland. AB25 2ZD. UK.
Background and purpose: Both CB(1) and CB(2) cannabinoid receptors have been shown to play a role in bone metabolism. Crucially, previous studies have focussed on the effects of cannabinoid ligands in murine bone cells. This study aimed to investigate the effects of cannabinoids on human bone cells in vitro. Experimental Approach: Quantitative RT-PCR was used to determine expression of cannabinoid receptors and liquid chromatography-electrospray ionisation tandem mass spectrometry was used to determine the presence of endocannabinoids in human bone cells. The effect of cannabinoids on human osteoclast formation, polarisation and resorption was determined by assessing the number of cells expressing a(v) β(3) or with F-actin rings, or measurement of resorption area. Key Results: Human osteoclasts express both CB(1) and CB(2) receptors. CB(2) expression was significantly higher in human monocytes compared to differentiated osteoclasts. Furthermore, the differentiation of human osteoclasts from monocytes was associated with a reduction in 2-AG levels and an increase in AEA levels. Treatment of osteoclasts with LPS significantly increased levels of AEA. Nanomolar concentrations of AEA and the synthetic agonists CP 55,940 and JWH015 stimulated human osteoclast polarisation and resorption; these effects were attenuated in the presence of CB(1) and/or CB(2) antagonists. Conclusions and Implications: Low concentrations of cannabinoids activate human osteoclasts in vitro. There is a dynamic regulation of the expression of the CB(2) receptor and the production of the endocannabinoids during the differentiation of human bone cells. The data suggest that small molecules modulating the endocannabinoid system may be important therapeutics in human bone disease.

Cannabinoids Stimulate Fibroblastic Colony Formation by Bone Marrow Cells Indirectly via CB2 Receptors
Recently, the cannabinoid receptors CB1 and CB2 were shown to modulate bone formation and resorptionin vivo, although little is known of the mechanisms underlying this. The effects of cannabinoids on mesenchymal stem cell (MSC) recruitment in whole bone marrow were investigated using either the fibroblastic colony-forming unit (CFU-f) assay or high-density cultures of whole bone marrow. Levels of the CB1 and CB2 receptors were assessed by flow cytometry. Treatment of CFU-f cultures with the endocannabinoid 2-arachidonylglycerol (2-AG) dose-dependently increased fibroblastic and differentiated colony formation along with colony size. The nonspecific agonists CP 55,940 and WIN 55,212 both increased colony numbers, as did the CB2 agonists BML190 and JWH015. The CB1-specific agonist ACEA had no effect, whereas the CB2 antagonist AM630 blocked the effect of the natural cannabinoid tetrahydrocannabivarin, confirming mediation via the CB2 receptor. Treatment of primary bone marrow cultures with 2-AG stimulated proliferation and collagen accumulation, whereas treatment of subcultures of MSC had no effect, suggesting that the target cell is not the MSC but an accessory cell present in bone marrow. Subcultures of MSCs were negative for CB1 and CB2 receptors as shown by flow cytometry, whereas whole bone marrow contained a small population of cells positive for both receptors. These data suggest that cannabinoids may stimulate the recruitment of MSCs from the bone marrow indirectly via an accessory cell and mediated via the CB2 receptor. This recruitment may be one mechanism responsible for the increased bone formation seen after cannabinoid treatment in vivo.

A functional link between the cannabinoid and opioid receptor pathways has been proposed based on data showing that cannabinoid effects can be blocked by opioid receptor antagonists and that cannabinoids can bind to opioid receptors. To explore this link in more detail at the receptor level, we tested the hypothesis that cannabinoids directly activate or modulate mu opioid receptor function. The G-protein coupled mu opioid receptor, MOR-1, and its effector, the G-protein activated potassium channel, GIRK2 (Kir3.2), were expressed together in Xenopus oocytes and potassium currents measured using the two-electrode voltage clamp technique. The specific mu receptor agonist DAMGO activated potassium currents in oocytes expressing the mu receptor that were fully inhibited by the mu receptor antagonist, naloxone. The endogenous cannabinoid, anandamide, and the synthetic cannabinoid, WIN 55,212-2, had no direct effects on potassium currents in the oocytes expressing the mu receptor. The cannabinoids also had no effect on the magnitude of the potassium currents activated by DAMGO or on the desensitization kinetics of MOR-1 in the continued presence of DAMGO. Both WIN 55,212-2 and anandamide activated cannabinoid CB1 receptors when co-expressed with GIRK2 in the oocytes. We conclude that neither anandamide nor WIN 55,212-2 directly activate or modulate mu opioid receptor function in oocytes and that interactions of cannabinoids with mu opioid receptors are likely to be indirect.

It seems cannabinoids deserve much more investigation, more money, more research and more case studies.
Medical marijuana does much to relieve many of the symptoms  associated with osteogenesis imperfecta.
Recommendation:  as an adjunct treatment for OI.  Taken as a whole plant extract:  tea, oil, tincture, edibles, vaporizer, butter.  Use a strain with high CBD levels in it.  (probably an Indica x hybrid)

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