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Osteogenic imperfecta


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This presentation details Osteogenic Imperfecta in its varying clinical manifestations in the population and offers a variety of adjunctive treatments not commonly used in OI management across the lifespan in order to decrease fracture, pain, and disability.

Published in: Health & Medicine
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Osteogenic imperfecta

  1. 1. By Kimmer Collison-Ris MSN, FNP-C, WOCN, MS CAM Images by Google Images
  2. 2. also known as 'brittle bone disease', clinically heterogeneous heritable connective tissue disorder collagen-related disorder characterized by low bone mass, decreased bone strength increased bone fragility The clinical features commonly include low bone mass + reduced bone material strength, results in bone fragility susceptibility to fracture, bone deformity and growth deficiency.
  3. 3. Incidence: occurs in approx 1 in 15,000-20,000 births,[1] mostly autosomal dominant inheritance. Over 1,500 dominant mutations in either COL1A1 or COL1A2, which encode the α-chains α1(I) and α2(I) of type I collagen
  4. 4. OI types range from types I-VIII Types I-IV are the most common Type II is typically fatal & infants don’t generally survive
  5. 5. Type Description Gene OMIM Comments I mild [Null COL1A1 allele] 166240(IA), 166200 (IB) II sev & usually fatal perinatally COL1A1, COL1A2, 166210 (IIA), 610854(IIB) III considered progressive and deforming COL1A1, COL1A2 259420 IV deforming, but with normal scleras COL1A1, COL1A2 166220 V shares the same clinical features of IV, but has unique histologic findings ("mesh-like") unknown 610967
  6. 6. Type Description Gene OMIM Comments VI shares the same clinical features of IV, but has unique histologic findings ("fish scale") unknown 610968 VII autosomal recessive, associated with cartilage associated protein CRTAP 610682 VIII severe to lethal, autosomal recessive, associated with the protein leprecan LEPRE1 610915
  7. 7. X-rays Gives clear images of bones, showing fractures Shows bone malformations Labs: blood or tissue samples Bone Density: bone densities every 6 months-1 year, to monitor bone strength. bone densities every 6 months-1 year, to monitor bone strength. genetic testing: Helps identify the mutation, esp. if parent's mutation is also known. Ultrasound can help detect severe cases of OI during pregnancy.
  8. 8. Testing for Risk of Recurrence: 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.
  9. 9. Families with one affected child are often concerned about the possibility of recurrence and should be referred for genetic counseling. Once a specific OI-causing mutation is identified through collagen biopsy or DNA analysis of the affected family member, further tests become possible. The child's biological parents can have DNA testing performed on a blood sample to determine whether 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.
  10. 10. Autosomal Dominant Mutant Type I Collagen Gene to Bone Defect. Mutations r are translated into collagen α-chains with abnormal structure in either, COL1A1 or COL1A2 delay folding of the heterotrimer result in excess post-translational modification of the collagen helical region.
  11. 11. Disease severity varies greatly. development of poor teeth below average height (short stature) Blue tint to the whites of their eyes (blue sclera) susceptible to fracture or multiple bone fractures Early hearing loss (deafness) loose joints (hypermobility) flat feet How well a person does depends on the type of OI they have.
  12. 12. Dentinogenesis imperfecta 1 (DGI1, MIM 125490) is an autosomal dominant dental disease characterized by abnormal dentin production and mineralization. Characterized by bone fragility & osteopenia. Most cases of OI are inherited as autosomal dominant traits & associated with mutations in one of the two genes encoding type I collagen (COL1A1, COL1A2).24
  13. 13. Autosomal recessive (AR) transmission of OI has been described in rare kindreds,1,4,5,8,9,27,28,30 but its recessive character is often difficult to distinguish from sporadic dominant mutations or somatic mosaicism. (M. LABUDA,1* J. MORISSETTE,2 L. M. WARD,1 F. RAUCH,1 L. LALIC,1 P. J. ROUGHLEY,1,3 and F. H. GLORIEUx 2002).
  14. 14. Type I collagen is formed from procollagen a heterotrimer composed of two proα1(I) and one proα2(I) chains, in which the helical collagen region is flanked by globular pro- domains at both the amino and carboxyl termini (Figure 1). The amino acid glycine is obligatory at every third helical residue (Gly-X-Y sequence) because of spatial constraints inside the triple helix. Procollagen is extensively hydroxylated and glycosylated post-translationally Mutations that cause dominant osteogenesis imperfecta alter the structure or quantity of type I collagen and cause a skeletal phenotype that ranges from subclinical to lethal.
  15. 15. Problem Meds Diet/Nutrients Specialists Lifestyle Mod Fragile bones Bisphosphamates Orthopedist Nutrition DSc Geneticist Family Practice Maintain healthy weight practice energy conservation low impact aerobic exercises: swimming Bone resorption Magnesium Protein Orthopedist Dental specialist Nutrition DSc Family Practice Low impact strengthening exercises Curved spine Vitamin D calcium Orthopedist Family Practice Physical Therapist Weak muscles Magnesium Protein Water Vitamin D Calcium Orthopedist Rehab Family Practice Nutrition DSc Low impact strengthening exercises
  16. 16. Problem Conventional Tx Diet/Nutrients Specialists Lifestyle Mod Bone pain Magnesium Calcium Potassium Vitamin D Orthopedist Nutrition DSc Muscle cramps/pain Magnesium Calcium Vitamin D Digestive Enzymes Orthopedist Family Practice Nutrition DSc Fallen arches (Flat feet) Orthopedist Podiatrist Loose ligaments & joints (hypermobility) Essential Fatty Acids Orthopedist Fatigue Increased water Ginseng Vitamin B complex Family Practice Hematologist
  17. 17. Problem Conventional Tx Diet/Nutrients Specialists Lifestyle Mod Below av ht Geneticist Endocrinologist Family Practice Orthopedist Kyphosis Bracing? Metal Rods Family Practice Orthopedist Posture Weight Bearing Exercises Scoliosis Bracing Metal Rods Family Practice Orthopedist Posture Weight Bearing Exercises Bowed arms/legs Family Practice Orthopedist Rehab
  18. 18. Problem Conventional tx Diet/Nutrients Specialists Lifestyle Mod Brittle teeth (dentinogenesis) Magnesium Calcium Vitamin D Dental Specialist Family Practice Nutrition DSc Avoid metal braces Avoid amalgams Avoid grinding Avoid hard candy/foods Avoid opening items w/teeth Avoid Implants Tooth erosion/wear Biotin? Calcium Magnesium Vitamin D Dental Specialist Family Practice Nutrition DSc Avoid soft dental guards-causes grinding Multiple cavities Garlic Echinacea Goldenseal Ginseng Dental Specialist Family Practice Nutrition DSc Lg pulp space Dental Specialist Family Practice
  19. 19. Problem Meds Diet/Nutrients Specialists Lifestyle Mod Gingivitis Vitamin C Garlic Echinacea Goldenseal Dental Specialist Family Practice Nutrition DSc Avoid soft dental guards-causes grinding Thin tooth enamel Bisphosphamates ? Calcium Vitamin D Magnesium Phosphorus? Dental Specialist Family Practice Nutrition DSc Avoid harsh tooth brushes Avoid tooth whiteners Use fluoride toothpastes don’t rinse toothpaste after brushing avoid sweetners & sugar drinks/candy avoid carbonated beverages Avoid granola
  20. 20. Problem Conventional Tx Diet/Nutrients Specialists Lifestyle Mod Easy bruising Vitamin C Vitamin K Family Practice Hematologist Frequent nosebleeds Vitamin C Vitamin K Family Practice Hematologist Blood coagulation problems Vitamin K Iron zinc Family Practice OB/GYN Geneticist Hematologist Heavy menses OC Vitamin K Iron zinc Family Practice OB/GYN Hematologist miscarriages Family Practice OB/GYN Geneticist
  21. 21. Problem Conventional Tx Diet/Nutrients Specialists Lifestyle Mod Fragile Skin Vitamin D Vitamin E Vitamin A Vitamin C Family practice Dermatology Nutrition DSc Early hearing loss Family Practice Audiologist Glaucoma Family Practice Opthamalogist Poor appetite Family Practice Nutrition DSc Family Practice Nutrition DSc Small frequent meals 80/20 alkaline & acid diet Avoid non- nutrient foods Whole foods diet Calcium rich foods (non-dairy)
  22. 22. Problem Conventional Tx Diet/Nutrients Specialists Lifestyle Mod Chest wall deformities Family Practice Orthopedist Pulmonologist Breathing problems Vitamin D Vitamin E Quercetin zinc Family Practice Pulmonologist Asthma Quercetin Vitamin D Stinging Nettle zinc Family Practice Pulmonologist
  23. 23. Observed in children and adults: Short stature Weak tissues, fragile skin, muscle weakness, loose joints Bleeding problems: easy bruising, frequent nosebleeds in a small number of people heavy bleeding from injuries Hearing loss may begin in childhood affects approximately 50% of adults Breathing problems higher incidence of asthma plus risk for other lung problems Curvature of the spine
  24. 24. largely based on the type of OI present. often directly related to the problems with weak bones & multiple fractures. Some include: Hearing loss (common in type I and type III) Heart failure (type II) Respiratory problems & pneumonias due to chest wall deformities Spinal cord or brain stem problems Permanent deformity
  25. 25. Should include multidisciplinary team: Family Practice CAM medical provider physical Therapy, Orthopedist Genetist, Audiology, Dental specialists, neurological, Endocrine Sports Medicine DSc Nutritionist Parents Teachers
  26. 26. Essential dietary nutrients: Protein, calcium, phosphorus, vitamin D Bone develop & maintenance: Vitamin C Bioflavonoids Increaseas Bone growth rate: vitamin A helps
  27. 27. Therapeutic Daily Dosage Vitamin C: Up to 5,000-mg Vitamin A as Beta Carotene: 25,000 IU Calcium: 1200-mg Magnesium 600-1200-mg Phosphorus: 400-mg Kelp Laminaria digitata Granules: 2-t Brewers Yeast: 2-T
  28. 28. Depending on the severity of OI, body size, and activity level, it may be necessary to reduce portion size, meal frequency, and total caloric intake to reach a healthy balance. Excessive weight gain should be avoided. Finding a healthy balance between calorie intake and exercise can be difficult.
  29. 29. Diet, herbal support, and exercise may be helpful to support medical treatment of OI To promote bone development & optimal health, children and adults with osteogenesis imperfecta (OI) should eat a balanced diet, low in fat, salt & added sugar Nutrient rich: contains a variety of vitamins & minerals.
  30. 30. blood and lymph fluids are maintained at 7.37 pH body will cannibalize bone matrix to extract alkalinity when starved for it. pH balance of stomach should range 2-4 pH Urine or saliva pH 2h pc pH should stabilize then fall to 6.5 - 7.0 Target is 6.5 in am (first urine draw) optimum kidney functioning a.m. urine <6.0 problematic 6.4 is perfect for critical ionization
  31. 31. Food and substance allergies can exacerbate inflammation and should be identified and avoided. Common food allergies are milk, beef, corn, and wheat, and common substances are dust, mold, and pollen. The nightshade vegetables -- tomato, potato, eggplant and pepper -- are also known to contribute to joint inflammation in sensitive individuals.
  32. 32. Diet evaluation whole-food organic diet high in vegetables & fruits balanced & nut rich, Cottage cheese w/o preservatives fermented products (sauerkraut) Soy isoflavones from soy protein Diet’s Essential Nutrients: protein, calcium, magnesium, manganese, fluoride, phosphorus, and vitamin D, K, C, essential fatty acids. Zinc, boron, & copper also important. Therapeutic supplements are necessary.
  33. 33. Weight reduction is essential. Alkaline diet includes: vegetables & fruits; small amounts of grains & dairy products. best to avoid: meat (high in uric acid), salt, sugar, and all preserved, colored, or processed, flavored food. Essential fatty acids prevent and reduce pain Eicosapentaenoic acid (EPA) is the main component of fish oils that provide this benefit. Fish with high levels of omega fatty acids (salmon & tuna). Pregnant woman and children should limit intake of tuna due to high levels of environmental mercury
  34. 34. good sources of these fatty acids Olive oil, flax seed Lignum usitatissimum, nuts, avocados Foods rich in folic acid, lentils, split peas, barley Hordeum vulgare, alfalfa Medicago sativa, soy, oats.
  35. 35. Vitamin C: up to 5,000 mg/day Vitamin D: Women <50y: 22 IU/day; women 50-70y: 400IU/day; women >70y: 600 IU/day; max daily dose < 2000IU/day* controversy exists re:upper limits of vitamin D leading to toxicity. Obtained from National Institutes of Health, Office of Dietary Supplements (, >10,000 IU/day reasonable w/o --toxicity. National Standard limits to 2,000 IU/day for all.
  36. 36. Vitamin A (as beta-carotene): 3,500 IU of vitamin A or 42,000IU of beta-carotene/day. Excessive levels of vitamin A poss linked --bone loss; beta-carotene – water soluble & carries less risk than retinol. Note: Women of child-bearing age <5,000 IU/d of preformed vitamin A (retinol) + effective birth control risk of birth defects linked to its use. Beta-carotene is a safer option. Brewers Yeast: 2-3-T Essential fatty acids: 3000-mg Flaxseed organic: 2-t ground fresh
  37. 37. Calcium citrate: 1200-mg, 1500-mg >50y each dose not >500-mg Magnesium: 600-mg, best if a 1:2 ratio w/calcium Vitamin E: 400-800 IU/day Kelp Laminaria digitata granules: 2-t Lecithin: 2-3-T
  38. 38. Sesame Seeds: ¼ c=351 mg. Spinach: 1 c boiled spinach=245 mg. Collard Greens: 1c boiled collard greens=266 mg. Blackstrap Molasses :1T=approx 137 mg. Kelp: 1c raw kelp =136 mg. Tahini (sesame seed butter): 2 T raw tahini = 126 mg. Broccoli: 2c boiled broccoli =124 mg. Swiss Chard: 1c boiled chard =102 mg. Kale: 1c boiled kale has 94 mg. Brazil Nuts: 2 oz Brazil nuts (12) =90 mg. Celery: 2 c raw celery =81 mg. Almonds: 1 oz=(23 nuts) =75 mg. Papaya: 1 med papaya =73 mg. Flax Seeds: 2T seeds=52 mg. Oranges: 1 med orange=52 mg.
  39. 39. CalciumRobbers Calcium can be negatively affected innocent foods. Salt-calcium excreted w/salt via kidneys Animal protein- meat, seafood, eggs and dairy Caffeine- calcium was only leached by those carbonated beverages containing caffeine Coffee approx. 4 c 2 chemicals that bind calcium & block ability to absorb Oxalates-found in spinach & rhubarb Phytates-found in bran & beans Examples of (-) food combos: Cheese sprinkled on a spinach salad milk poured over bran cereal.
  40. 40. VitaminD Vitamin D is a fat-soluble vitamin that is essential for maintaining normal calcium metabolism . Vitamin D3 (cholecalciferol) can be synthesized by humans in the skin upon exposure to ultraviolet-B (UVB) radiation from sunlight, or it can be obtained from the diet. Plants synthesize ergosterol, which is converted to vitamin D2 (ergocalciferol) by ultraviolet light . When exposure to UVB radiation is insufficient for the synthesis of adequate amounts of vitamin D3 in the skin, adequate intake of vitamin D from the diet is essential for health. Increased exposure to sunlight or increased dietary intake of vitamin D increases serum levels of 25-hydroxyvitamin D, making the serum 25-hydroxyvitamin D concentration a useful indicator of vitamin D nutritional status. Oregon State University, Linus Pauling Institute. (2012
  41. 41. People who have persistently low vitamin D levels may experience symptoms of fatigue, muscle aches or bone pain. Foods rich in Vitamin D: Salmon & fish Beef liver eggs Whole & skim cow milk Mushrooms Margarine Yogurt Swiss cheese Soy beverages
  42. 42. Low circulating vitamin D levels have been associated with an increased risk for osteoarthritis progression, increased joint space narrowing, and increased osteophyte growth[12].
  43. 43. Vitamin C: The Framingham epidemiological study found an association between low vitamin C levels and increased cartilage loss, as well as a reduction in the risk of osteoarthritis progress in those with the highest vitamin C levels[3]. A small, random, controlled trial of 1-g of the calcium ascobate form of vitamin C showed small effect of decreased pain[4]. Caution should be used with high dose vitamin C, especially in those with kidney disease or a history of kidney stones.
  44. 44. Green Chili Peppers: 1/2c chopped=181.88mg Red chillies : ½ c chopped=108mg Guavas: per fruit=126mg Bell Peppers (amount depends on color) Yellow peppers =341mg /pepper, Green peppers =132mg / pepper. Fresh Herbs (Thyme and Parsley) Thyme: 1 t =1.6mg. & Parsley : 1 T=5mg Dark Leafy Greens : 80mg =1 c chopped Broccoli: 81mg =1c chopped Kiwi Fruits: 1 c = 164 mg Papaya: 1 c cubed=81 mg Oranges: 1 med=83mg Strawberries: 1 c sliced=98mg
  45. 45. Vitamin E: The studies with vitamin E and osteoarthritis have had mixed results. Three small trials showed a decrease in knee pain but two larger, better designed studies did not show benefit in pain or knee architecture. Consider 400 IU of α-tocopherylacetate as part of a combination of antioxidants. Reactive oxygen species (ROS) produced in inflammatory processes like OA can overwhelm the antioxidant capacity of tissues, which can lead to increased cartilage degradation[5]. Antioxidants, such as vitamin C and E, can therefore be helpful.
  46. 46. SAMe (s-adenosylmethionine): The effects of SAMe on both pain and function may be potentially clinically relevant based on the results from a few small clinical trials[6]. According to American Family Physician, the Butanedisulfonate salt form is preferred for best stability and bioavailability, at 200-mg three times daily[7]. Avoid with serotonergic[8] anti-depressants.
  47. 47. Weight reduction is essential. alkaline diet includes: vegetables and fruits ;small amounts of grains & dairy products. best to avoid : meat (high in uric acid), salt, sugar, all preserved, colored, or processed, flavored food. Essential fatty acids important for prevention and pain reduction. Eicosapentaenoic acid (EPA) is the main component of fish oils that provide this benefit. Fish with high levels of omega fatty acids such as salmon and tuna are helpful. However, due to high levels of environmental mercury, particularly pregnant woman and children should limit intake of tuna..
  48. 48. Glucosamine Sulfate and Chondrotin Sulfate: More than 20 randomized, controlled trials involving over 2,500 patients have evaluated the use of glucosamine for osteoarthritis. While the form of glucosamine can make a difference and the effects seem best for knee pain, the overall consensus is that GS is effective in reducing pain, improving function, and even decreasing joint space narrowing. Glucosamine sulfate is preferred over glucosamine hydrochloride, at 1,500-mg once daily or 500-mg three times daily.
  49. 49. Research also shows that glucosamine may increase insulin levels[9]. Increased insulin levels are associated with elevated triglycerides, cholesterol, and blood pressure. Caution clients at risk for diabetes, hypertension, or hyperlipidemia (an excess of lipids in the plasma), and recommend frequent blood glucose, serum lipids, and blood pressure monitoring. Glucosamine is derived from shellfish, so should be avoided by clients allergic to shellfish. The evidence for chondroitin is inconsistent and harvested from animal sources. Studies have shown combination chondroitin/glucosamine to be no better than glucosamine sulfate alone[10].
  50. 50. Most Americans are Omega-3 deficient because of our over-processed diets, Found in foods Flaxseed oil (highest linolenic content), flaxseeds, flaxseed meal, hempseed oil, hempseeds, walnuts, pumpkin seeds, Brazil nuts, sesame seeds, avocados,
  51. 51. Magnesium strengthens nerves natural tranquilizer. strengthens bones, Strengthens tissues, aids blood circulation. Herbs may help in tooth decay, irritability, poor circulation, insomnia, acidity.
  52. 52. Foods: Bran (Rice, Wheat, and Oat) Dried herbs: corriender, chives, spearmint, dill, sage, basil, savory Squash, Pumpkin, and Watermelon Seeds Cocoa Powder (Dark Chocolate) Flax, Sesame Seeds, and Sesame Butter Brazil Nuts Sunflower Seeds Almonds and Cashews (Mixed nuts, Pine Nuts) Molasses Dry Roasted Soybeans (Edamame)
  53. 53. High doses: magnesium Phosphorous zinc can prompt excessive urinary excretion ---depletion. Antibiotics (some) anti-seizure medications diuretics Steroids Alcohol Mineral oil interfere w/absorption should be dosed 1/2 h before or 2 h Ca++ or meals
  54. 54. Low Back Pain symptoms Moderate exercise should be done each day to strengthen and tone the area. Abdominal exercises are especially beneficial to prevent future occurrence of this problem. Posture is also important. Standing the client against a wall can make an approximate check. If the posture is correct only the shoulders and buttocks should touch the wall. Encourage the client to improve the posture if necessary. Yoga is excellent when posture requires improvement. If pain persists for more than a few days or is accompanied by shooting pains down one or both legs, seek medical attention, as there may be a herniated disc that can cause nerve damage.
  55. 55. Essential in: bone & teeth conditions impoverished blood asthma obesity nervous conditions to increase endurance and vitality Begin Protocols before Porotic bone symptoms & degeneration worsen once symptoms worsen, clients can be assisted via diet & herbal therapy Nutrient Tx Includes: calcium phosphorus magnesium
  56. 56. Weight bearing exercise (walking or weight lifting) shown to stimulate production of new bone. strengthens muscle that supports improves balance --- preventing falls. Studies illustrate exercise helps reverse physical illnesses.
  57. 57. Therapeutic exercise should aim to strengthen the muscles that move the joints in order to take the strain off the ligaments. Ligament strains commonly cause pain around joints. Exercise should also increase the range of movement in an arthritic joint. Swimming is one of the best exercises for anyone with arthritis as it takes the weight off all the joints and tones and strengthens the muscles.
  58. 58. Epsom Salts Packs Hot Epsom salt packs will also relieve pain and congestion around the joints.
  59. 59. Cramps generally result from: over-exertion, anxiety, stress. Low nutrient intake/absorption from sitting/standing in an unnatural position, restricts blood flow to extremities. Cramps may be due to Dehydration deficiency in calcium, magnesium, vitamin C, vitamin B1.
  60. 60. Gentle Massage Application of castor oil packs An acute cramp in a muscle that is accessible will respond to a massage w/1% dilution of wormwood Artemisia absinthium essential oil wintergreen Gaultheria procumbens essential oil in a base oil.
  61. 61. Regular massage with vegetable oil mixed with essential oil of sassafras Sassafras albidum helps to reduce inflammation and pain. Caution: avoid w/peanut allergies Cayenne Liniment: 1-2-T of Cayenne Capsicum anuum pepper 1-cup white or apple cider vinegar 1-cup boiling water Steep the ingredients for 30 minutes strain and bottle. Massage the liniment into the painful areas after a hot bath or shower. Follow up by massaging with hot olive oil. Repeat two to three times a day.
  62. 62. Extraordinary Liniment: Bay Laurus nobilis essential oil 30 drops Clove Syzygium aromaticum essential oil 5 drops Cajuput Melaleuca leucadendron var. cajuputi essential oil 10 drops Cypress Cupressus sempervirens essential oil 10 drops Peanut oil 1 cup (avoid in allergies) Blend all ingredients and massage painful areas at least once a day.
  63. 63. A 2008 three-month, double-blind, and placebo-controlled study[1] conducted by the Chieti-Pescara University evaluated the effectiveness of using 100 mg capsules of Pycnogencol daily with osteoarthritis patients. Pycnogenol[2] is a natural plant extract from the bark of the maritime pine tree, which grows exclusively along the coast of southwest France in Les Landes de Gascogne. Methods: Osteoarthritis symptoms were evaluated by WOMAC (Western Ontario and McMaster Osteoarthritis Index) scores: The treatment group (77 patients) and the placebo group (79 control) were compared for age, sex, WOMAC scores, walking distances, and use of anti-inflammatory drugs. Results: edema decreased in 79% of Pycnogenol patients and 1% of the control group + treatment group was able to decr use anti-inflam meds, walk farther (treadmill), & suffered less gastrointestinal issues. Conclusion: Pycnogenol may be a good alternative to anti-inflammatory drugs and will not only provide relief from treatment costs, but also drug side effects. utcome_score_womac.html.
  64. 64. [1] Chrubasik S, Eisenberg E, Balan E, et al. Treatment of low back pain exacerbation with willow bark extract: a randomized double-blind study. C Am J Med 2000; 109(1): 9-14. [2] For a useful discussion of this issue, review Clauson KA, Santamarina ML, Buettner CM, Cauffield JS, Evaluation of presence of aspirin related warnings with willow bark, Ann Pharmacother 2005 Jul-Aug; 39(7-8):1234-7 Epub 2005 May 31 [3] Boullata JI, McDonnell PJ, Oliva CD. Anaphylactic reaction to a dietary supplement containing willow bark. Ann Pharmacother 2003;37:832-835. [4] However, plant salicylates are structurally different, and do not appear to interact with blood coagulants. Wichtl MW. Herbal Drugs and Phytopharmaceuticals. Stuttgart: Medpharm GmbH Scientific Publishers; 1994. [5] Labeling for oral and rectal over-the-counter drug products containing aspirin and nonaspirin saliciylates; Reyes syndrome warning Final Rule Fed Regist 2003 Apr 17;68(74):18861-9 Accessed at PubMed May 2, 2006 [6] Linus Pauling Institute. [7] Mortensen P Charles (1996). Conditions to treat osteoporosis. March 1996 vol. 63 no. 3 354- 357.] [8] from [9]Roger Bouillon, Geert Carmeliet, Lieve Verlinden, Evelyne van Etten, Annemieke Verstuyf, Hilary F. Luderer, Liesbet Lieben, Chantal Mathieu and Marie Demay. Vitamin D and Human Health: Lessons from Vitamin D Receptor Null Mice. Endocrine Reviews October 1, 2008 vol. 29 no. 6 726-776. doi: 10.1210/er.2008-0004. Retrieved from]
  65. 65. [10] [Heaney, R.P., Dowell, S.M., Hale, C.A. ,and Bendich, A. (2003). Calcium Absorption Varies within the Reference Range for Serum 25-Hydroxyvitamin D J Am Coll Nutr April 2003 vol. 22 no. 2 142-146] [11] [Merja UM Kärkkäinen, Christel JE Lamberg-Allardt, Suvi Ahonen and Matti Välimäki (2001). Does it make a difference how and when you take your calcium? The acute effects of calcium on calcium and bone metabolism Am J Clin Nutr September 2001 vol. 74 no. 3 335-342] [12] [Michael F Holick. (2004) Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. American Journal of Clinical Nutrition, Vol. 80, No. 6, 1678S-1688S, December 2004.