Vitamin D

Common Names: Vitamin D; Calciferol, Cholecalciferol, Ergocalciferol

Clinical Name: 1,25 dihydroxycholecalciferol

Summary

Vitamin D

forms: Calciferol, cholecalciferol, ergocalciferol, irradiated ergosterol.

overview of interactions:
• nutrient affecting drug performance: Calcium Channel Blockers

• nutrient affected by drug: Cholestyramine

• nutrient affected by drug: Cimetidine

• nutrients affected by drug: Colestipol

• nutrients (Vitamin D and Calcium) affected by drug: Corticosteroids, including Prednisone

• nutrient affected by drug: Glucocorticoids

• nutrients (Vitamin D and Calcium) affected by drug: Heparin

• nutrient affected by drug: Isoniazid

• nutrient affected by drug: Mineral Oil

• nutrient affected by drug: Phenobarbital

• nutrient affected by drug: Phenytoin (Dilantin®)

• nutrient affected by drug: Thiazide Diuretics

• nutrient affecting drug performance: Verapamil

• nutrient affecting drug performance and toxicity: Warfarin

chemistry:
• Vitamin D (cholecalciferol) is stable to heat, light, and storage.
• Vitamin D2 (ergocalciferol) is obtained from plants.
• Vitamin D3 is cholecalciferol derived from animal products.
• Calcitriol is the name of a drug which is the active (1,25 dihydroxycholecalciferol) form of vitamin D.

metabolism:
• Vitamin D can be synthesized in the skin with the aid of ultraviolet light. It is estimated that the RDA can be achieved with the exposure of 30% of a persons skin surface for 30 minutes at moderate latitudes.
• Vitamin D is absorbed from the small intestine in the presence of bile and is transported into the circulation via the lymph in chylomicrons (similar to vitamin A transport).
• Vitamin D is stored in the liver, bone, brain, and skin.

function:
• Vitamin can be considered both a vitamin and a hormone.
• Vitamin D plays an important role in maintaining adequate blood levels of insulin and may assist the metabolism of sugar.
• 1,25 dihydroxycholecalciferol (DHCC), the most active form of vitamin D, functions to:
» Increase the absorption of calcium from the intestines by stimulating the synthesis of calcium-binding protein. This occurs in the brush border of the intestinal mucosa.
» Increase the resorption of calcium from bone.
» Increase serum calcium levels. Once this occurs calcium can then be stored in the bones. Thus, even though it initially causes bone resorption, the net effect is to increase calcium deposition in the bone.

sources:
• Sunshine: With exposure to ultraviolet light the skin synthesizes vitamin D. It is estimated that 20 minutes, with face and arms exposed, will stimulate about 200 I.U. per day. A moderate sunburn can produce 10,000 I.U. per day. Significant amounts of vitamin D can be synthesized and stored to carry through the winter.
• Dietary sources: Cod liver oil, cold water fish (salmon, mackerel, herring), butter, egg yolks.
Vitamin D is found primarily in foods of animal origin, unless they are fortified. Vegetables are usually low in vitamin D. Leafy dark green vegetables and mushrooms are significant sources of vitamin D from non-animal sources. Milk used to make cheese or yogurt is usually not fortified with vitamin D. Human milk contains the 25 hydroxycholecalciferol form of D probably because the liver in infants is not that functional for the first hydroxylation of cholecalciferol. The vitamin D in human milk varies with sun exposure and vitamin D intake.

deficiency:
• In 1997 Chapuy et al reported that one out of seven adults may be deficient in vitamin D. Likewise, a study in 1998 by Thomas et al found that 37% of the total group surveyed were deficient in vitamin D even though their reported diets should have provided the currently recommended levels of vitamin. This study also found that 42% of hospitalized patients under the age of sixty-five were deficient in vitamin D.
• Rickets: In children a deficiency of vitamin D causes rickets, a malformation of the bones due to decreased deposition of calcium phosphate (hydroxyapatite). The signs and symptoms of this disease in young infants are restlessness, poor sleep and reduced mineralization of the skull away from the sutures. In older infants, sitting and crawling are delayed; bossing of the skull and costochondral beading (rachitic rosary) occur. There is also enlargement of epiphyseal growth plates, especially noted in the radius and ulna. Failure of the fontanels to close results in a large head with delayed teeth eruption, stunted growth, bow legs or knock knees.
• Osteomalacia: Deficiency of vitamin D in adults causes osteomalacia, a skeletal demineralization especially in the spine, pelvis, and lower extremities. Signs and symptoms of osteomalacia are burning mouth and throat, nervousness, diarrhea, and insomnia.
• Etiology: Alcoholics, Crohn's disease, Cushing's disease, dark skin, decreased consumption of vitamin D, hypothyroidism, individuals on anticonvulsive drug therapy, following intestinal surgery, kidney or liver disease, malabsorption (as in celiac disease), poor exposure to sun, ulcerative colitis, vitamin D-resistant rickets.

known or potential therapeutic uses: Cancer prevention, celiac disease, diabetes mellitus, fractures (especially in the elderly), migraine headaches, osteomalacia (especially associated with Crohn’s disease), osteoporosis, prevention of vitamin D deficiency, psoriasis, rickets.

maintenance dose: 400 IU per day. However, this may be unnecessary with adequate direct exposure to the sun.
• RDA:
200 IU for adults
400 IU for children, adolescents and pregnant or lactating women
400 - 800 IU for individuals, especially the elderly, not adequately exposed to sunlight or living in farther northern or southern latitudes.

Requirements depend upon the exposure of a persons skin to ultraviolet radiation. The intensity of exposure is also a factor. The latitude at which a person lives, determines how much exposure to sunlight the person requires to synthesize adequate levels of vitamin D. Pollution, clouds, and skin color also affect an individual's ability to produce vitamin D. The darker the skin, the less vitamin D will be produced (95% blocked). However, if longer exposure times are had, even with the darkest skin color, sufficient levels of vitamin D are produced. Glass blocks UV light.

therapeutic dose: 800 - 2,000 IU per day, including dietary sources, under supervision of a physician or healthcare professional experienced in nutritional therapies.

side effects:
• Excessive levels of vitamin D intake over an extended period can lead to headaches, kidney stones, and weight loss. Less common symptoms include diarrhea, increased thirst, increased urination, irritability, failure to gain weight in children. More extreme consequences include blindness, deafness, and, potentially, death.
• Vitamin D intake increases both calcium and phosphorus absorption. While the increased levels of calcium associated with enhanced vitamin D status may be an indicator of benefit for those at risk for bone loss, elevated blood levels of calcium may also be associated with increased risk of heart disease.
• Vitamin D intake may contribute to increased absorption of aluminum.
• Concerned has been raised that vitamin D could potentially contribute to a slight elevation of cholesterol levels.

toxicity:
• Acute overdose: increased frequency in urination, nausea, vomiting, loss of appetite, diarrhea, muscle weakness, dizziness, calcification of heart, blood vessels and lungs; symptoms reverse after overdosing is discontinued.

Children:
• Vitamin D intakes of 2,000 IU to 3,000 IU per day may cause toxicity symptoms in some children. Also, some hypersensitive infants have developed toxicity symptoms at 1,000 IU per day.
Most cases of toxicity involve the intake of 25,000-60,000 IU per day for 1-4 months.
• Children taking 10,000 IU per day for 4 months can develop the following toxicity symptoms:
headaches, weakness, nausea and vomiting, constipation, polyuria, polydipsia, diarrhea, and calcification of soft tissues such as kidneys, lungs, tympanic membrane or ears.

note: Large doses of vitamin A given concurrently with vitamin D tend to reduce the toxic effects of vitamin D.
(Kummerow FA, et al. Am J Clin Nutr. 1976 May;29(5):579-584; Kamio A, et al. Arch Pathol Lab Med 1977; 101: 378.)

contraindications:
• Sarcoidosis who have elevated blood levels of calcium.
• Hyperparathyroidism.



Interactions

nutrient affecting drug performance: Calcium Channel Blockers

• mechanism: Supplementation with vitamin D may interfere with the therapeutic effectiveness of verapamil.
(Threlkeld DS, ed. Nov 1992; Fox J, Della-Santina CP. Am J Physiol 1989 Nov;257(5 Pt 1):E632-638.)

• nutritional concerns: Individuals taking calcium channel blockers, especially verapamil, should consult their prescribing physician and/or a nutritionally trained healthcare professional before using supplements containing vitamin D.

nutrient affected by drug: Cholestyramine

• mechanism: Bile acid sequestrants, such as cholestyramine, decrease lipid digestion and absorption, as well as absorption of the fat-soluble vitamins and other nutrients.
(Roe DA. 1985: 158-159; Watkins DW, et al. Dig Dis Sci 1985 May;30(5):477-482; Hathcock JN. Fed Proc. 1985 Jan;44(1 Pt 1):124-129; West RJ, Lloyd JK. Gut. 1975 Feb;16(2):93-98.)

• nutritional support: Regular use of a high-potency multiple vitamin/mineral will replace the nutrients impeded by the drug.

nutrient affected by drug: Cimetidine

• mechanism: Cimetidine reduces the liver's ability to activate vitamin D through hydroxylation.

• nutritional support: Lab tests can determine blood levels of 25(OH)cholecalciferol, the activated form of vitamin D. If too low, a prescription for an activated form of vitamin D would be required as activation of a regular vitamin D supplement would be vulnerable to blockage by the cimetidine.

nutrient affected by drug: Colestipol; along with Vitamin A, Vitamin E, Vitamin K and Folate

• mechanism: Colestipol, by design, reduces fat absorption and hence interferes with absorption of fat-soluble nutrients.
(Tonstad S, et al. Arch Dis Child 1996 Feb;74(2):157-160.)

• clinical concerns: This interaction raises serious questions given the accumulating experimental, epidemiological, and clinical evidence of an association between anti-oxidant vitamin intake and reduced risk of coronary heart disease.

• research: Hodis et al have reported an association between supplementary vitamin E intake and angiographically demonstrated reduction in coronary artery lesion progression. Tonstad et al conducted a study of 37 boys and 29 girls aged 10-16 years with familial hypercholesterolaemia first in an eight week double blind, placebo controlled protocol, then in open treatment for 44-52 weeks. They found that levels of serum folate, vitamin E, and carotenoids were reduced in the colestipol group. After one year of colestipol, those who took 80% or moreof the prescribed dose had a greater decrease in serum 25-hydroxyvitamin D levels than those who took less than 80%.
(Hodis HN, et al. JAMA 1995 Jun 21;273(23):1849-1854; Tonstad S, et al. Arch Dis Child 1996 Feb;74(2):157-160.)

• nutritional support: Vitamin D supplementation, with a safe dosage for a typical adult being 400 IU per day, is recommended for individuals taking colestipol. Making sure one gets adequate exposure to the direct sunlight is the easiest way to maintain healthy levels of active vitamin D.

nutrients (Vitamin D and Calcium) affected by drug: Corticosteroids, including Prednisone

• mechanism: Steroidal anti-inflammatory drugs interferes with the body’s ability to activate vitamin D and thus cause greater risk of bone loss. Under active transport conditions, administration of cortisone produces a decrease of net calcium absorption through two mechanisms: (1) depressed vitamin D-dependent calcium absorption, (2) increased vitamin D-independent calcium backflux. (Yeh JK, et al. Calcif Tissue Int 1984 Sep;36(5):608-614.) In a 1998 study Lems et al reported that low-dose (10 mg/day) prednisone (LDP) treatment led to a decrease in osteocalcin, P1CP and alkaline phosphatase and an increase in urinary excretion of calcium. They concluded that LDP has a negative effect on bone metabolism, since bone formation decreased while bone resorption remained unchanged or decreased slightly.
(Lems WF, et al. Br J Rheumatol 1998 Jan;37(1):27-33; Pronsky, Z. 1991, 60.)

• research: Studies on a wide range of corticosteroids have established the usefulness of calcium and vitamin D supplements in the treatment and the prevention of steroid-induced osteoporosis. In particular, the adverse effects of glucoactive corticosteroids on intestinal calcium transport and bone turnover can usually be counteracted by the combined administration of supplemental doses of calcium and physiological doses of 25OHD3.
(Yeh JK, et al. Calcif Tissue Int 1984 Sep;36(5):608-614; O'Regan S, et al. Acta Paediatr Scand 1979 Jan;68(1):109-111; Trovato A et al. Am Family Phys 1991;44:1651-1658; Chesney RW et al. Lancet 1978;ii:1123-1125; Lund B, et al. Clin Endocrinol (Oxf) 1977 Dec;7 Suppl:177s-181s; Nuti R, et al. J Endocrinol Invest 1984 Oct;7(5):445-448.)

In one study individuals using low doses of prednisone as treatment for rheumatoid arthritis maintained their bone density when they also took daily supplement doses of 1,000 mg (1 gram) of calcium and 500 IU of vitamin D. (Buckley LM, et al. Ann Intern Med 1996;125:961-968.)

In a more recent study with low-dose prednisone, Lems et al found parathyroid hormone (PTH) (insignificantly) increased during LDP (+19%) and LDP plus calcium (+14%), but decreased during supplementation with calcitriol (-16%) and calcium/calcitriol (-44%). The increase in PTH during LDP could be prevented by calcitriol combined with calcium supplementation.
(Lems WF, et al. Br J Rheumatol 1998 Jan;37(1):27-33.)

• nutritional support: Individuals using corticosteroids for periods longer than two weeks should discuss the nutritional implications with their prescribing physician and/or a nutritionally trained healthcare professional. In particular, supplementation of vitamin D and calcium should be considered. Most research supports the benefit of taking daily supplemental doses of 1,000-1,500 mg (1-1.5 gram) of calcium and 500 IU of vitamin D. Individuals using corticosteroids for an extended period of time might consult with their prescribing physician about laboratory testing of levels of 1,25 dihydroxycholecalciferol, the activated form of vitamin D. If a deficiency is discovered, activated vitamin D can be obtained by prescription as "calcitriol."

The importance of mild-to-moderate exercise in the prevention of osteoporosis cannot be overemphasized. However, individuals with known or potential bone loss are advised to develop an exercise program under the supervision of a physician or other healthcare professional familiar with the increased risks of fracture associated with long-term use of steroids.

nutrient affected by drug: Glucocorticoids

• mechanism: Glucocorticoid drugs may decrease vitamin D availability and lower serum 25-hydrosycalciferol levels.
(Hodges R. 1980:323-331; Hahn TJ, et al. N Engl J Med. 1972 Nov 2;287(18):900-904.)

• nutritional support: Most research supports the benefit of taking daily supplemental doses of 500 IU of vitamin D. Individuals using glucorticoids for an extended period of time might consult with their prescribing physician about laboratory testing of levels of 1,25 dihydroxycholecalciferol, the activated form of vitamin D. If a deficiency is discovered, activated vitamin D can be obtained by prescription as "calcitriol."

nutrients (Vitamin D and Calcium) affected by drug: Heparin

• mechanism: Heparin interferes with the ability of the kidneys to activate vitamin D. Over time heparin causes bone loss, especially in the spine, hips, pelvis and legs.

• research: Majerus et al reported that use of heparin, at high doses, for a period of several months has been found to cause osteoporosis. Likewise both Wise and Hall, and later Haram et al, found that women who received heparin therapy during pregnancy experienced decreased bone density (Osteopenia). On the other hand, in one study nine women on heparin treatment received 6.46 g daily of a special calcium preparation OHC (ossein-hydroxyapatite-compound) over a period of six months and were compared to eleven women not receiving the bone protective treatment. In the OHC-group, good compliance was observed with no side effects and reduced back pain. Those taking the calcium preparation did not demonstrate the expected decreases in bone mass, while bone mass dropped significantly in the controls.
(Dahlman T, et al. Br J Obstet Gynaecol. 1990 Mar;97(3):221-228; Majerus PW, et al. 1996, 1346; Ringe JD, et al. Geburtshilfe Frauenheilkd 1992 Jul;52(7):426-429: Wise PH, Hall AS. BMJ 1980;281:110-111; Haram K, et al. Acta Obstet Gynecol Scand 1993;72:674-675.)

• nutritional support: There is no definitive pattern in the research confirming the benefits of supplementing vitamin D and calcium in individuals on heparin for any extended period. However, in the meantime, such supplementation could be beneficial and is not contraindicated. Individuals taking heparin should consult their physician and/or a healthcare provider trained in nutrition before they institute a program supplementation with vitamin D or calcium. With chronic use, tests can be done to measure l,25(OH)₂ cholecalciferol levels. If low, calcitriol should be supplemented.

nutrient affected by drug: Isoniazid

• mechanism: Research indicates that antituberculous drugs, including isoniazid, induce vitamin D deficiency. Vitamin D levels have been found to be lowered in children with tuberculosis, untreated and using isoniazid.

• nutritional support: Vitamin D supplementation may be of great value in addition to antituberculous drugs in the treatment of tuberculous children, and its use is highly recommended. Exposure to sunlight is the simplest and most natural way to provide activated vitamin D; it might be noted that sunshine and mountain air were characteristic of the great sanitoriums. However, when vitamin D is to be supplemented orally, the typical dosage would be in the range of 200-400 IU per day, depending on size and body weight. It is important to remember that excessive vitamin D can be harmful; though toxicity due to accumulation would be unlikely in this patient population, especially at doses less than 1,000 IU per day.
(Morcos MM, et al. Boll Chim Farm 1998 May;137(5):157-164.)

nutrient affected by drug: Mineral Oil

• mechanism: Mineral oil, as a lipid solvent, may absorb many substances and/or interfere with normal absorption of vitamin D and other nutrients.

• research: While there is some disagreement, most research has found that mineral oil interferes with the absorption of many nutrients, including beta-carotene, calcium, phosphorus, potassium, and vitamins A, D, K, and E. Chronic use of mineral oil can cause a deficiency of vitamins A, D, E, and K, being fat soluble, as a result of their being absorbed.
(Holt GA.1998, 176.)

• nutritional concerns: If using mineral oil for any extended period of time, regular use of a multivitamin supplement would be beneficial. Malabsorption of fat-soluble vitamins due to ingestion of mineral oil can be minimized by administering mineral oil on an empty stomach or consuming vitamin or mineral supplements at least two hours before or after the mineral oil. In general it is advisable to limit the internal use of mineral oil to periods of less than one week.

nutrient affected by drug: Phenobarbital

• mechanism: Phenobarbital impairs bioavailability of vitamin D.

• research: Phenobarbital and other anticonvulsants are inducers of cytochrome P-450 and the mixed-function oxidase system. Thus, anticonvulsants impair mineralisation, leading to osteomalacia and osteoporosis. Long-term treatment can cause excessive metabolism and deficiency of vitamin D and is believed to be associated with decreased bone mineral density and bone loss. After finding no pattern of low serum levels of vitamin D (25[OH]D) or radiologic evidence of osteomalacia or rickets in over 400 individuals using anticonvulsants in Florida, Williams et al concluded that the climate provided adequate exposure to sunshine and thereby prevented the development of anticonvulsant-induced osteomalacia or rickets.
(Holmes RP, Kummerow FA. J Am Coll Nutr. 1983;2(2):173-199; D'Erasmo E, et al. Recenti Prog Med 1998 Oct;89(10):529-533; Chung S, Ahn C. Brain Dev 1994 Sep-Oct;16(5):382-385; Pluskiewicz W, Nowakowska J. Ultrasound Med Biol 1997;23(4):553-558; Bone HG. JAMA 1983;249:939; Williams C, et al. Southern Med J 1984 Jul;77(7):834-836, 842; Livingston S. JAMA 1983;249:939; Jones G, Sambrook PN. Drug Saf 1994 Jun;10(6):480-489.)

• nutritional support: A moderate dose of 400-1500 IU per day of vitamin D could exert a protective function for individuals using phenobarbital who are concerned about potential drug-induced osteoporosis. However, as suggested above, regular exposure to sunlight might provide adequate stimulation to enable the body to produce necessary levels of vitamin D. Others have advocated a proactive approach toward the risks of bone loss while voicing caution that given the increased risk of osteomalacia among those taking anticonvulsants, withdrawal from such drugs carries potential for increased risk of seizure-related fractures.
(Tomita S, et al. J Steroid Biochem Mol Biol 1991 Oct;39(4A):479-485; Christiansen C, et al. Br Med J 1973 Dec 22;4(894):695-701; Macallan DC, et al. Postgrad Med J 1992 Feb;68(796):134-136; Duus BR. Injury 1986 Jan;17(1):31-33.)

nutrient affected by drug: Phenytoin (Dilantin®)

• research: Bone loss has been associated with phenytoin therapy and is considered to be due to phenytoin's interference with vitamin D metabolism. Phenytoin and other anticonvulsants are inducers of cytochrome P-450 and the mixed-function oxidase system. Thus, anticonvulsants impair mineralisation, leading to osteomalacia and osteoporosis. Long-term treatment can cause excessive metabolism and deficiency of vitamin D and is believed to be associated with decreased bone mineral density and bone loss. Usually lab tests will reveal elevated Alk Phos levels and mild hypocalcemia. After finding no pattern of low serum levels of vitamin D (25[OH]D) or radiologic evidence of osteomalacia or rickets in over 400 individuals using anticonvulsants in Florida, Williams et al concluded that the climate provided adequate exposure to sunshine and thereby prevented the development of anticonvulsant-induced osteomalacia or rickets.
(D'Erasmo E, et al. Recenti Prog Med 1998 Oct;89(10):529-533; Chung S, Ahn C. Brain Dev 1994 Sep-Oct;16(5):382-385; Pluskiewicz W, Nowakowska J. Ultrasound Med Biol 1997;23(4):553-558; Bone HG. JAMA 1983;249:939; Williams C, et al. Southern Med J 1984 Jul;77(7):834-836, 842; Livingston S. JAMA 1983;249:939; Jones G, Sambrook PN. Drug Saf 1994 Jun;10(6):480-489.)

• nutritional support: A moderate dose of 400-1500 IU per day of vitamin D could exert a protective function for individuals using phenytoin who are concerned about potential drug-induced rickets or osteoporosis. However, as suggested above, regular exposure to sunlight might provide adequate stimulation to enable the body to produce necessary levels of vitamin D. Others have advocated a proactive approach toward the risks of bone loss while voicing caution that given the increased risk of osteomalacia among those taking anticonvulsants, withdrawal from such drugs carries potential for increased risk of seizure-related fractures.
(Tomita S, et al. J Steroid Biochem Mol Biol 1991 Oct;39(4A):479-485; Christiansen C, et al. Br Med J 1973 Dec 22;4(894):695-701; Macallan DC, et al. Postgrad Med J 1992 Feb;68(796):134-136; Duus BR. Injury 1986 Jan;17(1):31-33; Bone HG. JAMA 1983;249:939.)

nutrient affected by drug: Thiazide Diuretics

• mechanism: When thiazide diuretics decrease calcium excretion they, in turn, exert an influence on vitamin D metabolism.

• nutritional concerns: Given the uncertainty of such implications, individuals taking these drugs are advised to consult their prescribing physician and/or a nutritionally-trained healthcare provider before starting or increasing any Vitamin D supplementation.
(Seligmann H, et al. Am J Med 1991 Aug;91(2):151-155.)


nutrient affecting drug performance: Verapamil

• mechanism: Supplementation with vitamin D may interfere with the therapeutic effectiveness of verapamil.
(Threlkeld DS, ed. Nov 1992; Fox J, Della-Santina CP. Am J Physiol 1989 Nov;257(5 Pt 1):E632-638.)

• nutritional concerns: Individuals taking verapamil should consult their prescribing physician and/or a nutritionally trained healthcare professional before using supplements containing vitamin D.

nutrient affecting drug performance and toxicity: Warfarin

• report: Concern has been raised about a possible dangerous interaction between vitamin D and anticoagulant medicines such as warfarin. The potential for increased activity of anticoagulants due to vitamin D has not been confirmed by any substantial research.
(Schrogie JJ. JAMA 1975;232:19.)

• nutritional concerns: Individuals using warfarin should be aware of the theoretical risk of enhanced drug activity when taking vitamin D. Even though the occurrence of this interaction would seem to be widespread if it represented a significant risk, concerned patients should consult their prescribing physician before beginning supplementation with vitamin D in doses greater than 400 IU per day.

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Do not rely solely on the information in this article.

References

Aaron JE, Gallagher JC, Anderson J, Stasiak L, Longton EB, Nordin BE, Nicholson M. Frequency of osteomalacia and osteoporosis in fractures of the proximal femur. Lancet. 1974 Feb 16;1(7851):229-233.

Aarskog D, Aksnes L, Lehmann V. Low 1,25-dihydroxyvitamin D in heparin-induced osteopenia. Lancet 1980 Sep 20;2(8195 Pt 1):650-651. (Letter)

Aarskog D, Aksnes L, Markestad T, Ulstein M, Sagen N. Heparin-induced inhibition of 1,25-dihydroxyvitamin D formation. Am J Obstet Gynecol 1984 Apr 15;148(8):1141-1142.

Bays HE, Dujovne CA.  Drug interactions of lipid-altering drugs. Drug Saf. 1998 Nov;19(5):355-371. (Review)

Bengoa JM, Bolt MJ, Rosenberg IH. Hepatic vitamin D 25-hydroxylase inhibition by cimetidine and isoniazid. J Lab Clin Med 1984 Oct;104(4):546-552.

Bone HG. Long-term anticonvulsant therapy and vitamin D metabolism. JAMA 1983;249:939. (Review)

Boucher BJ. Inadequate vitamin D status: does it contribute to the disorders comprising syndrome ‘X’? Br J Nutr 1998;79:315-327.

Brodie MJ, Boobis AR, Hillyard CJ, Abeyasekera G, Stevenson JC, MacIntyre I, Park BK. Effect of rifampicin and isoniazid on vitamin D metabolism. Clin Pharmacol Ther 1982 Oct;32(4):525-530.
Abstract: Rifampicin, 600 mg, and isoniazid, 300 mg daily for 14 days, reduced circulating levels of 25-hydroxy vitamin D (25-OHD) and 1 alpha, 25-dihydroxy vitamin D (1,25(OH)2D) by 34% (P less than 0.01) and 23% (P less than 0.05) in eight healthy subjects. This was accompanied by a rise in parathyroid hormone (PTH) of 57% (P less than 0.01), but not by a fall in serum calcium or phosphate levels. There was induction of endogenous cortisol oxidation in all subjects, but only in four fast acetylators was there a concomitant increase in antipyrine elimination. In the four slow acetylators antipyrine metabolism was inhibited after the first dose of the drugs. In nine tuberculous patients followed serially there was a fall in 25-OHD and 1,25 (OD)2D and a rise in PTH at the end of 1 mo (P less than 0.05). After 6 mo therapy 25-OHD concentration was further reduced (P less than 0.01), but there was no significant change in 1,25 (OH)2D or PTH levels. Combination treatment with rifampicin and isoniazid perturbs vitamin D metabolism, but less than might have been predicted from reports on each drug given alone. Nevertheless, tuberculous patients with already compromised calcium homeostasis receiving this combination of drugs should be carefully monitored.

Buckley LM, Leib ES, Cartularo KS, Vacek PM, Cooper SM. Calcium and vitamin D3 supplementation prevents bone loss in the spine secondary to low-dose corticosteroids in patients with rheumatoid arthritis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1996 Dec 15;125(12):961-968.
Abstract: BACKGROUND: Therapy with low-dose corticosteroids is commonly used to treat allergic and autoimmune diseases. Long-term use of corticosteroids can lead to loss of bone mineral density and higher risk for vertebral fractures. Calcium and vitamin D3 supplementation is rational therapy for minimizing bone loss, but little evidence for its effectiveness exists. OBJECTIVE: To assess 1) the effects of supplemental calcium and vitamin D3 on bone mineral density of patients with rheumatoid arthritis and 2) the relation between the effects of this supplementation and corticosteroid use. DESIGN: 2-year randomized, double-blind, placebo-controlled trial. SETTING: University outpatient-care facility. PATIENTS: 96 patients with rheumatoid arthritis, 65 of whom were receiving treatment with corticosteroids (mean dosage, 5.6 mg/d). INTERVENTION: Calcium carbonate (1000 mg/d) and vitamin D3 (500 IU/d) or placebo. MEASUREMENTS: Bone mineral densities of the lumbar spine and femur were determined annually. RESULTS: Patients receiving prednisone therapy who were given placebo lost bone mineral density in the lumbar spine and trochanter at a rate of 2.0% and 0.9% per year, respectively. Patients receiving prednisone therapy who were given calcium and vitamin D3 gained bone mineral density in the lumbar spine and trochanter at a rate of 0.72% (P = 0.005) and 0.85% (P = 0.024) per year, respectively. In patients receiving prednisone therapy, bone mineral densities of the femoral neck and the Ward triangle did not increase significantly with calcium and vitamin D3. Calcium and vitamin D3 did not improve bone mineral density at any site in patients who were not receiving corticosteroids. CONCLUSION: Calcium and vitamin D3 prevented loss of bone mineral density in the lumbar spine and trochanter in patients with rheumatoid arthritis who were treated with low-dose corticosteroids.

Buist RA. Drug-nutrient interactions - an overview. Intl Clin Nutr Rev 1984;4(3):114. (Review)

Camici M. Dialysis-associated bone disease. JAMA 1986 Sep 19;256(11):1447. (Letter)

Chapuy MC, Preziosi P, Maamer M, Arnaud S, Galan P, Hercberg S, Meunier PJ. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporosis Int 1997;7(5):439-443.
Abstract: The vitamin D status of a general adult urban population was estimated between November and April in 1569 subjects selected from 20 French cities grouped in nine geographical regions (between latitude 43 degrees and 51 degrees N). Major differences in 25-hydroxyvitamin D (25(OH)D) concentration were found between regions, the lowest values being seen in the North and the greatest in the South, with a significant 'sun' effect (r = 0.72; p = 0.03) and latitude effect (r = -0.79; p = 0.01). In this healthy adult population, 14% of subjects exhibited 25(OH)D values < or = 30 nmol/l (12 ng/ml), which represents the lower limit (< 2 SD) for a normal adult population measured in winter with the same method (RIA Incstar). A significant negative correlation was found between serum intact parathyroid hormone (iPTH) and serum 25(OH)D values (p < 0.01). Serum iPTH held a stable plateau level at 36 pg/ml as long as serum 25(OH)D values were higher than 78 nmol/l (31 ng/ml), but increased when the serum 25(OH)D value fell below this. When the 25(OH)D concentration became equal to or lower than 11.3 nmol/l (4.6 ng/ml), the PTH values reached the upper limit of normal values (55 pg/ml) found in vitamin D replete subjects. These results showed that in French normal adults living in an urban environment with a lack of direct exposure to sunshine, diet failed to provide an adequate amount of vitamin D. It is important to pay attention to this rather high prevalence of vitamin D insufficiency in the general adult population and to discuss the clinical utility of winter supplementation with low doses of vitamin D.

Chesney RW, Mazess RB, Hamstra AJ, DeLuca HF, O'Reagan S. Reduction of serum-1,25-dihydroxyvitamin-D, in children receiving glucocorticoids. Lancet 1978 Nov 25;2(8100):1123-1125.
Abstract: Serum-1,25-dihydroxyvitamin-D3 (1,25-[OH]2D3) was subnormal in children receiving long-term glucocorticoid treatment for various glomerular diseases, including nephrotic syndrome. In children with chronic glomerulonephritis not treated with glucocorticoids who had similar serum-creatinine with glucocorticoids who had similar serum-creatinine concentrations, serum-1,25-dihydroxyvitamin-D3 concentrations resembled those in healthy controls, indicating that glomerular renal disease per se does not account for reduced serum-1,25(OH)2DE concentrations in steroid-treated patients. The reduction in concentration of this most active vitamin-D metabolite correlated with the dose of steroid administered and with reduction in forearm bone mineral content measured by the photon absorption technique. Reduced serum-1,25-(OH)2D3 concentration may be important in the pathogenesis of steroid-induced osteopenia.

Christiansen C, Rodbro P, Lund M. Incidence of anticonvulsant osteomalacia and effect of vitamin D: controlled therapeutic trial. Br Med J 1973 Dec 22;4(894):695-701.

Chung S, Ahn C. Effects of anti-epileptic drug therapy on bone mineral density in ambulatory epileptic children. Brain Dev 1994 Sep-Oct;16(5):382-385.
Abstract: In order to assess the bone changes in the subjects receiving anti-epileptic drugs (AEDs), bone mineral densities (BMDs) of the arms, legs, ribs, pelvis, spine, and the whole body were scanned in 78 epileptic children and in 78 controls using dual photon absorptiometry. The study subjects were classified according to the duration of the monotherapy with phenobarbital (PB) or phenytoin (PHT); those who received AEDs for less than 12 months as Group I, for 13-23 months as Group II, and for 24 months as Group III. Group III was subclassified according to the kind of AEDs administered, into those receiving PB as Group IIIp, and those receiving PHT as Group IIId. There was no significant differences in the BMDs of each area, when compared to each control in Groups I and II. In Group III, there were significant differences in ribs and spine, according to the duration of administration. In Group IIIp, there was a significant difference in ribs and spine, and, in Group IIId, there was a significant difference in most of the areas. These results show that the measurement of BMDs in the ribs and spine is necessary for the early detection of subtle bone loss, and it is recommended that vitamin D be administered to children with epilepsy receiving AEDs over 24 months.

Collins N, Maher J, Cole M, Baker M, Callaghan N. A prospective study to evaluate the dose of vitamin D required to correct low 25-hydroxyvitamin D levels, calcium, and alkaline phosphatase in patients at risk of developing antiepileptic drug-induced osteomalacia. Q J Med 1991 Feb;78(286):113-122.
Abstract: The dose of vitamin D3 required to maintain normal serum 25-hydroxyvitamin D levels in epileptic patients was evaluated in a prospective study. Patients were divided into two groups, comprising 14 institutionalized and 18 non-institutionalized subjects; they were taking carbamazepine, phenytoin and phenobarbitone, alone or in combination. The study was divided into a dose titration stage and a further period of assessment on a fixed dose after attainment of normal serum 25-hydroxyvitamin D levels. Seventeen of the 18 non-institutionalized patients achieved normal levels over a period of 12 months; the remaining patient became normal after 15 months. The dose required to achieve normal levels ranged from 400 to 4000 IU/day; three patients required less than 2400 IU vitamin D3, 12 required 2400 IU and three required greater than 2400 IU. All institutionalized patients achieved normal levels over a period of 12 months; six patients required less than 2400 IU, six required 2400 IU and two required greater than 2400 IU vitamin D3. Raised alkaline phosphatase levels occurred in 11 patients, and reverted to normal in six patients during the initial return of 25-hydroxyvitamin D levels to normal. During the second 12 months, when patients were taking a fixed dose of vitamin D3, alkaline phosphatase increased in five patients who had achieved normal levels. During this phase normal 25-hydroxyvitamin D levels were not maintained in five patients. There was a significant seasonal variation of 25-hydroxyvitamin D levels institutionalized patients, being highest in June and lowest in December. Our findings show that while there was a wide range in the dose required to achieve normal serum 25-hydroxyvitamin D levels--between 400 and 4000 IU/day--78 per cent of patients responded to a dose of 2400 IU/day.

Dahlman T, Lindvall N, Hellgren M. Osteopenia in pregnancy during long-term heparin treatment: a radiological study post partum. Br J Obstet Gynaecol. 1990 Mar;97(3):221-228.
Abstract: Osteopenia, sometimes with compression fractures of the spine, is a side-effect of long-term heparin treatment. The frequency is unknown. In this study, 70 women were given subcutaneous heparin as therapy for, or prophylaxis against, thromboembolism during pregnancy. All, except two, were examined by X-ray of the spine and hip first week post partum. The duration of treatment and the dosage of heparin varied. There were 12 (17%) with obvious osteopenia, including two women with multiple fractures of the spine (3%). Re-examination 6-12 months post partum showed that the changes were reversible in most cases. Another 18 women were examined about three years after heparin treatment during pregnancy. No obvious osteopenia was found among them or in a control group of 30 women examined in the first week post partum. The degree of osteopenia was not correlated with either the heparin dose or the duration of treatment. Women treated with heparin in consecutive pregnancies do not seem to have an increased risk of osteopenia.

Dawson-Hughes B, Harris SS, Krall EA, Dallal GE, Falconer G, Green CL. Rates of bone loss in postmenopausal women randomly assigned to one of two dosages of vitamin D. Am J Clin Nutr 1995 May;61(5):1140-1145.
Abstract: We conducted a study to determine whether increasing vitamin D intake above the recommended dietary allowance (RDA) of 5.0 micrograms (200 IU)/d reduces bone loss in healthy postmenopausal women residing at latitude 42 degrees N. In this double-blind, randomized 2-y trial, we enrolled 247 healthy ambulatory postmenopausal women who consumed an average of 2.5 micrograms (100 IU) vitamin D/d in their usual diets. The women were given either 2.5 micrograms (100 IU) or 17.5 micrograms (700 IU) vitamin D/d. All women received 500 mg supplemental calcium per day as citrate malate. Duplicate hip and spine and single whole-body scans were performed by dual-energy x-ray absorptiometry at 6-mo intervals selected to flank the periods when 25-hydroxycholecalciferol (calcidiol) concentrations are highest (summer/fall) and lowest (winter/spring). Plasma calcidiol and serum osteocalcin were measured in these seasons in year 1. Both treatment groups lost bone mineral density from the femoral neck, but the 17.5-micrograms group lost less than (-1.06 +/- 0.34%; mean +/- SE) the 2.5-micrograms group (-2.54 +/- 0.37%, P = 0.003). Seventy percent of the benefit each year occurred in winter/spring and 30% in summer/fall. Changes in spinal and whole-body bone densities did not differ by treatment group and were minimal after 2 y. Serum osteocalcin and plasma calcidiol (2.5-micrograms group only) fluctuated with season. In conclusion, in healthy, calcium-supplemented, postmenopausal women residing at latitude 42 degrees N, an intake of 5.0 micrograms (200 IU) vitamin D/d is sufficient to limit bone loss from the spine and whole body but it is not adequate to minimize bone loss from the femoral neck.

D'Erasmo E, Ragno A, Raejntroph N, Pisani D. [Drug-induced osteomalacia]. Recenti Prog Med 1998 Oct;89(10):529-533. [Article in Italian] (Review)
Abstract: The osteomalacia is a metabolic bone disease, characterized by a defect of bone mineralization, due to a lot of causes; among these an important role may be attributed to some drugs. The drugs most frequently associated with osteomalacia are: cholestyramine, phenytoin, phenobarbital, rifampicin, isoniazid, aluminium-containing antacid, saccharated ferric oxide, cadmium, lead, bisphosphonates, fluoride and aluminum. In this review we discuss about the pathophysiologic mechanisms related to drug-induced osteomalacia involving vitamin D metabolism, phosphorus homeostasis and bone mineralization.

Devgun MS, Paterson CR, Johnson BE, Cohen C. Vitamin D nutrition in relation to season and occupation. Am J Clin Nutr 1981 Aug;34(8):1501-1504.?
Abstract: Seasonal variations in vitamin D nutrition were assessed by measurements of serum 25-hydroxycholecalciferol levels in outdoor workers, indoor workers and long-term hospital inpatients. All three groups showed seasonal changes and the outdoor workers had, as might be expected, the highest levels at all seasons. However, the highest levels of 25-hydroxycholecalciferol were found in October in the indoor workers and in November for the outdoor workers whereas the peak in ultraviolet exposure was in July. The possible reasons for this long lag are discussed; the most likely explanation is that vitamin D continues to be formed and stored during the autumn especially in outdoor workers.

Duus BR Fractures caused by epileptic seizures and epileptic osteomalacia. Injury 1986 Jan;17(1):31-33.
Abstract: A case of several severe fractures in one patient following epileptic seizures is reported. The patient suffered from epileptic osteomalacia and responded well to vitamin D treatment. The cause of anticonvulsant-induced osteomalacia and its treatment are discussed.

Farmer JA, Gotto AM Jr. Choosing the right lipid-regulating agent. A guide to selection. Drugs 1996 Nov;52(5):649-661.
Fox J, Della-Santina CP. Oral verapamil and calcium and vitamin D metabolism in rats: effect of dietary calcium. Am J Physiol 1989 Nov;257(5 Pt 1):E632-638.

Farmer JA, Gotto AM Jr. Antihyperlipidaemic agents. Drug interactions of clinical significance. Drug Saf 1994 Nov;11(5):301-309.
Abstract: The available antihyperlipidaemic drugs are generally safe and effective, and major systemic adverse effects are uncommon. However, because of their complex mechanisms of action, careful monitoring is required to identify and correct potential drug interactions. Bile acid sequestrants are the most difficult of these agents to administer concomitantly, because their nonspecific binding results in decreased bioavailability of a number of other drugs, including thiazide diuretics, digitalis preparations, beta-blockers, coumarin anticoagulants, thyroid hormones, fibric acid derivatives and certain oral antihyperglycaemia agents. Although the incidence is low, nicotinic acid may cause hepatic necrosis and so should not be used with drugs that adversely affect hepatic structure or function. With the HMG-CoA reductase inhibitors, relatively new agents for which clinical data are still being accumulated, the major problems appears to be rhabdomyolysis, associated with the concomitant use of cyclosporin, fibric acid derivatives or erythromycin, and mild, intermittent hepatic abnormalities that may be potentiated by other hepatotoxic drugs. Fibrates also have the potential to cause rhabdomyolysis, although generally only in combination with HMG-CoA reductase inhibitors, and are subject to binding by concomitantly administered bile acid sequestrants. The major interaction involving probucol is a possible additive effect with drugs or clinical conditions that alter the prolongation of the QTc interval, increasing the potential for polymorphic ventricular tachycardia.

Garland C, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH, Paul O. Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men. Lancet. 1985 Feb 9;1(8424):307-309.
Abstract: Mortality rates from colon cancer in the USA are highest in populations exposed to the least amounts of natural sunlight; differences in endogenous vitamin D production and calcium absorption could be responsible. To investigate this possibility, the association of dietary vitamin D and calcium with 19-year risk of colorectal cancer was examined in 1954 men who had completed detailed, 28-day dietary histories in the period 1957-59. Risk of colorectal cancer was inversely correlated with dietary vitamin D and calcium. In the quartiles of a combined index of dietary vitamin D and calcium, from lowest to highest, observed risks of colorectal cancer were 38.9, 24.5, 22.5, and 14.3/1000 population. This association remained significant after adjustment for age, daily cigarette consumption, body mass index, ethanol consumption, and percentage of calories obtained from fat.

Gough H, Goggin T, Bissessar A, Baker M, Crowley M, Callaghan N. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in out-patients with epilepsy. Q J Med 1986 Jun;59(230):569-577.
Abstract: The biochemical parameters associated with vitamin D metabolism, calcium, 25-hydroxy-vitamin D (25OHD) and alkaline phosphatase levels were assessed in 226 out-patients with epilepsy. Patients were grouped depending on the drug treatment; carbamazepine, phenytoin, phenobarbitone and sodium valproate used alone as monotherapy and a combination of these drugs as polytherapy. The most severe alterations occurred in the polytherapy group. Hypocalcaemia was more severe in the phenobarbitone monotherapy group than the carbamazepine or the phenytoin groups. No patient on sodium valproate monotherapy had subnormal levels of calcium (less than 2.1 mmol/l). 25OHD levels were similarly reduced in the carbamazepine, phenytoin and the phenobarbitone groups with no reduction in the sodium valproate group. Significant elevations in alkaline phosphatase levels were evident in all patient groups except the sodium valproate group. This study confirms biochemical evidence for anticonvulsant osteomalacia when the enzyme-inducing drugs are used, the degree of severity depending on the drug regimen.

Hahn M, Lorez H, Fischer G. Effect of calcitriol in combination with corticosterone, interleukin-1beta, and transforming growth factor-beta1 on nerve growth factor secretion in an astroglial cell line. J Neurochem 1997 Jul;69(1):102-109.
Abstract: In astrocytes, nerve growth factor (NGF) synthesis has been described to be stimulated by the cytokines interleukin-1beta (IL-1beta) and transforming growth factor-beta1 (TGF-beta1) and inhibited by corticosterone. As all three factors are present in the brain under certain conditions, we investigated the effect of their combined application on NGF secretion in the astroglial cell line RC7 and, in addition, studied the effect of calcitriol (1alpha,25-dihydroxyvitamin D3). Calcitriol stimulated NGF secretion, whereas corticosterone reduced basal levels of NGF secretion as well as inhibited the NGF secretion induced by IL-1beta, calcitriol, and TGF-beta1. Calcitriol had an additive effect when applied together with IL-1beta and a synergistic effect when applied with TGF-beta1. Moreover, calcitriol not only counteracted the inhibitory effect of corticosterone on NGF secretion stimulated by TGF-beta1 but even augmented it to a level more than threefold higher than that reached with TGF-beta1 alone. Due to the trophic effect of NGF on basal forebrain cholinergic neurons, these findings might be of therapeutic relevance under conditions where cholinergic function is impaired and the endogenous levels of corticosterone, IL-1beta, or TGF-beta1 are elevated.

Hahn TJ, Hendin BA, Scharp CR, Haddad JG Jr. Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults. N Engl J Med. 1972 Nov 2;287(18):900-904.

Haram K, Hervig T, Thordarson H, Aksnes L. Osteopenia caused by heparin treatment in pregnancy. Acta Obstet Gynecol Scand 1993 Nov;72(8):674-675.
Abstract: A case is reported of severe osteopenia caused by heparin treatment of thrombosis in the eleventh week of pregnancy followed by heparin prophylaxis (5000 IU three times daily) during pregnancy and lactation. The mother complained of back pain during the last two weeks of pregnancy. Six weeks post partum, generalized osteopenia in the skeleton was diagnosed and a compression fracture of the body of the sixth thoracic vertebra. During pregnancy the mother had relatively low serum concentrations of 1,25(OH)2D, the active metabolite of vitamin D, and six weeks after delivery the serum concentration had fallen to about 50% of the lowest reference level. Eight and fourteen weeks after delivery, when heparin treatment had been discontinued, the serum concentrations of 1,25(OH)2D were within the reference range for non-pregnant adults.

Hathcock JN. Metabolic mechanisms of drug-nutrient interactions. Fed Proc 1985 Jan;44(1 Pt 1):124-129.
Abstract: Metabolic mechanisms of nutrition and drug interactions include 1) the effects of diet on drug metabolism and action and 2) the effects of drugs on nutritional processes. The type, amount, and timing of foods consumed influence drug dissolution, absorption, distribution, metabolism, and excretion. High-fat meals enhance the absorption of griseofulvin and some other drugs. Milk and other sources of calcium inhibit absorption of tetracycline. High-fat meals increase plasma concentrations of free fatty acids and thereby displace many drugs from binding sites on plasma albumin. High-protein diets increase the activity of the mixed-function oxidase system and enhance the metabolism of numerous drugs. High-electrolyte intakes increase excretion of lithium and also diminish the action of diuretic agents. Bile acid sequestrants and some laxatives decrease lipid digestion and absorption, as well as absorption of the fat-soluble vitamins. Numerous drugs, including tetracycline and cholestyramine, bind iron and decrease its absorption. Coumarins inhibit the function of vitamin K. Phenobarbital and other anticonvulsants are inducers of cytochrome P-450 and the mixed-function oxidase system. Long-term treatment with these inducers can cause excessive metabolism and deficiency of vitamin D. Prooxidant drugs such as chloroquine, drugs detoxified by conjugation with glutathione, and alcohol can deplete reduced glutathione with consequent effects on amino acid transport and the redox status of cells. Acid-forming foods acidify the urine and increase the loss of alkaline drugs such as the amphetamines. Base-forming drugs increase the loss of acidic drugs such as barbiturates. The range of metabolic interactions of drugs and nutrients includes the full scope of physiological processes to which drugs and nutrients are subject.

Hayes CE, Cantorna MT, Deluca HF. Vitamin D and multiple sclerosis. Proc Soc Exper Biol Med 1997;216:21-27. (Review)

Heikkinen AM, Tuppurainen MT, Niskanen L, Komulainen M, Penttila I, Saarikoski S. Long-term vitamin D3 supplementation may have adverse effects on serum lipids during postmenopausal hormone replacement therapy. Eur J Endocrinol 1997 Nov;137(5):495-502.
Abstract: OBJECTIVE: The positive short-term effects of postmenopausal hormone replacement therapy (HRT) on serum lipids are well known, but it has been suggested that they vanish with time. Cholecalciferol (vitamin D3) is widely used to prevent postmenopausal osteoporosis but the influence of vitamin D3 on serum lipids is poorly known. The long-term effects of HRT and vitamin D3 on the concentrations of serum lipids were studied in a population-based prospective 3-year study. DESIGN AND METHODS: 464 women were randomized into four treatment groups: (i) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate), (ii) Vit D3 (vitamin D3 300 IU/day), (iii) HRT+Vit D3 (both as above), (iv) placebo (calcium lactate 500 mg/day). RESULTS: 320 women completed the study. After three years of treatment, serum concentrations of low density lipoprotein (LDL) cholesterol decreased in the HRT group (10.1%, P<0.001) and the HRT+Vit D3 group (5.9%, P=0.005), increased in the Vit D3 group (4.1%, P=0.035) but remained unchanged in the placebo group. The concentrations of total cholesterol decreased by 5.8% in the HRT group (P<0.001) and by 3.3% in the HRT+Vit D3 group (P=0.023), but did not change in the other two groups. Serum concentrations of high density lipoprotein (HDL) cholesterol decreased in the Vit D3 group (5.2%, P=0.001), HRT+Vit D3 group (3.7%, P=0.046), and the placebo group (4.5%, P=0.006) but did not change significantly in the HRT group. The HDL/LDL ratio increased in the HRT group (10.5%, P=0.006) and decreased in the Vit D3 group (10.5%, P<0.001) whereas no changes occurred in the other two groups. In addition, serum triglycerides increased similarly in all groups (14.0-18.8%, P<0.05-0.001). CONCLUSIONS: Our results confirm the positive long-term effect of HRT with sequential estradiol valerate and cyproterone acetate on serum lipid concentrations. In addition, the results suggest that vitamin D3 supplementation may have unfavorable effects on lipids in postmenopausal women. Pure vitamin D3 treatment was associated with increased serum LDL cholesterol. Furthermore, the beneficial effects of HRT on serum LDL cholesterol content were reduced when estradiol valerate was combined with vitamin D3. However, the relevance of these associations to cardiovascular morbidity remains to be established.

Hodges R. Drug-nutrient interaction, In: Nutrition in Medical Practice. Philadelphia: W.B. Saunders, 1980:323-331.

Hodis HN, Mack WJ, LaBree L, Cashin-Hemphill L, Sevanian A, Johnson R, Azen SP. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA 1995 Jun 21;273(23):1849-1854.
Abstract: OBJECTIVE--To explore the association of supplementary and dietary vitamin E and C intake with the progression of coronary artery disease. DESIGN--A subgroup analysis of the on-trial antioxidant vitamin intake database acquired in the Cholesterol Lowering Atherosclerosis Study, a randomized, placebo-controlled, serial angiographic clinical trial evaluating the risk and benefit of colestipol-niacin on coronary artery disease progression. SETTING--Community- and university-based cardiac catheterization laboratories. SUBJECTS--A total of 156 men aged 40 to 59 years with previous coronary artery bypass graft surgery. INTERVENTION--Supplementary and dietary vitamin E and C intake (nonrandomized) in association with cholesterol-lowering diet and either colestipol-niacin or placebo (randomized). OUTCOME--Change per subject in the percentage of vessel diameter obstructed because of stenosis (%S) determined by quantitative coronary angiography after 2 years of randomized therapy on all lesions, mild/moderate lesions (< 50%S), and severe lesions (> or = 50%S). RESULTS--Overall, subjects with supplementary vitamin E intake of 100 IU per day or greater demonstrated less coronary artery lesion progression than did subjects with supplementary vitamin E intake less than 100 IU per day for all lesions (P = .04) and for mild/moderate lesions (P = .01). Within the drug group, benefit of supplementary vitamin E intake was found for all lesions (P = .02) and mild/moderate lesions (P = .01). Within the placebo group, benefit of supplementary vitamin E intake was not found. No benefit was found for use of supplementary vitamin C exclusively or in conjunction with supplementary vitamin E, use of multivitamins, or increased dietary intake of vitamin E or vitamin C. CONCLUSIONS--These results indicate an association between supplementary vitamin E intake and angiographically demonstrated reduction in coronary artery lesion progression. Verification from carefully designed, randomized, serial arterial imaging end point trials is needed.

Holmes RP, Kummerow FA. The relationship of adequate and excessive intake of vitamin D to health and disease. J Am Coll Nutr. 1983;2(2):173-199. (Review)

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998.

Hoogwerf BJ, Hibbard DM, Hunninghake DB. Effects of long-term cholestyramine administration on vitamin D and parathormone levels in middle-aged men with hypercholesterolemia. J Lab Clin Med 1992 Apr;119(4):407-411.
Abstract: The objective of this study was to evaluate possible adverse effects of long-term bile acid-binding resin (cholestyramine) treatment on vitamin D, parathyroid hormone, and calcium levels in middle-aged men. A double-blind randomized clinical trial was carried out over a period of 7 to 10 years at the University of Minnesota's Lipid Research Clinic as part of the Lipid Research Clinic's Coronary Primary Prevention Trial. Two hundred and sixty-eight men aged 42 to 68 years who had been previously randomized in the CPPT to cholestyramine or placebo and who had taken at least 75% of the prescribed study medication (6 packets or 24 gm/day) as determined by packet counts for the duration of the Coronary Primary Prevention Trial including the last 4 months of the trial were studied: one group (n = 124) received cholestyramine and the other group (n = 144) received a corresponding dose of placebo. Serum samples were obtained at the time of the final study visit in cholestyramine and placebo groups. (Results are reported as mean +/- SD in SI units). There were no differences in plasma levels of calcium (2.3 +/- 0.1 mmol/L vs 2.3 +/- 0.1 mmol/L), phosphorus (0.99 +/- 0.14 mmol/L vs 0.98 +/- 0.12 mmol/L), albumin (45 +/- 3 gm/L vs 46 +/- 0.6 gm/L), calcifediol (62.6 +/- 29.2 nmol/L vs 63.4 +/- 28.4), 25(OH)D2 (14 +/- 11 nmol/L vs 12 +/- 10 nmol/L) or calcitriol (99 +/- 190 pmol/L vs 91 +/- 56 pmol/L).

Hudson JQ, Small RE, Buckley L. J Am Pharm Assoc (Wash) 1998 Nov-Dec;38(6):710-716. Perceptions of pharmacists about adverse effects of corticosteroid therapy: focus on osteoporosis.
Abstract: OBJECTIVE: To assess the perceptions of pharmacists regarding the adverse effects of corticosteroids, in particular corticosteroid-induced osteoporosis. DESIGN: Mailed survey of a random sample of pharmacists. SETTING: Richmond, Virginia. PARTICIPANTS: 350 community and hospital pharmacists. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Respondents' knowledge of adverse effects of corticosteroid therapy in men, premenopausal women, and postmenopausal women; the content of respondents' usual patient counseling for low- and high-dose therapy; and respondents' opinions of regimens for prevention of osteoporosis. RESULTS: Pharmacists associated gastritis, weight gain, and mood changes with corticosteroid use in a hypothetical 45-year-old man or 45-year-old premenopausal woman. For a hypothetical 65-year-old postmenopausal woman, pharmacists more frequently counseled about weight gain, osteoporosis, and gastritis. Patient counseling focused on these adverse effects for both low-dose (5 to 10 mg/day) and high-dose (> or = 30 mg/day) prednisone use. Osteoporosis was considered more likely in patients receiving high-dose corticosteroids on a long-term basis. CONCLUSION: Pharmacists responding to this survey frequently overlooked the association between low- and high-dose corticosteroid use and decreased bone density. Educational efforts are needed so that pharmacists can fulfill their potential for educating patients, monitoring corticosteroid therapy, and detecting drug-induced complications.

Ismail F, Corder CN, Epstein S, Barbi G, Thomas S. Effects of pravastatin and cholestyramine on circulating levels of parathyroid hormone and vitamin D metabolites. Clin Ther 1990 Sep-Oct;12(5):427-430.
Abstract: The subjects were 40 hypercholesterolemic patients (mean age, 58 years) receiving a low-fat diet and randomly assigned to treatment with placebo for eight weeks or 40 or 80 mg of pravastatin, 24 gm of cholestyramine, or 40 mg of pravastatin plus 24 gm of cholestyramine daily for 24 weeks. After eight weeks of active treatment, levels of total and low-density lipoprotein cholesterol were significantly reduced and the decline was maintained for the remaining 16 weeks. Parathyroid hormone levels and levels of the vitamin D metabolites 1,25(OH)2D3 and 25(OH)D3 did not change during treatment. The results indicate that 24 weeks of treatment with pravastatin and cholestyramine does not affect calcium metabolism.

Iivanainen M, Savolainen H. Side effects of phenobarbital and phenytoin during long-term treatment of epilepsy. Acta Neurol Scand Suppl 1983;97:49-67.
Abstract: Phenobarbital and phenytoin have good antiepileptic effect, but clinically significant untoward effects occur during their long-term use. Phenobarbital may cause hyperactivity, behavioral problems, sedation, and even dementia; these effects are dose related to some extent. Side effects of phenytoin include sedation, a cerebellar syndrome, phenytoin encephalopathy, psychosis, locomotor dysfunction, hyperkinesia, megaloblastic anemia, decreased serum folate level, decreased bone mineral content, liver disease, IgA deficiency, gingival hyperplasia, and a lupus-like hypersensitivity syndrome. Especially susceptible to the neurotoxic effects of phenytoin are epileptic children with severe brain damage who are on multiple drugs. In those children, balance disturbance may develop and be followed by gradual loss of locomotion. Among 131 mentally retarded epileptic patients, phenytoin intoxication occurred in 73 (56%), of whom 18 experienced persistent loss of locomotion. There is experimental evidence that the toxic action of phenytoin lies at the cellular level, predominantly in the cerebellum. Many experts avoid the long-term use of phenytoin because of its insidious and potentially dangerous side effects.

Jones G, Sambrook PN. Drug-induced disorders of bone metabolism. Incidence, management and avoidance. Drug Saf 1994 Jun;10(6):480-489.
Abstract: Calcium homeostasis depends upon the interplay of intestinal calcium absorption, renal excretion and skeletal mobilisation of calcium, mediated through bone formation and resorption, which are closely coupled in the adult skeleton. Serum calcium is extremely important for maintenance of normal cellular functions and is regulated by the major calciotropic hormones, parathyroid hormone (PTH), 1,25-dihydroxy-vitamin D and calcitonin. Certain drugs can interfere with calcium metabolism by effects at different stages in calcium metabolism, and a knowledge of the mechanism of drug action is generally helpful in understanding the various resultant clinical skeletal syndromes. Corticosteroids, for example, have profound effects at multiple stages of calcium metabolism, resulting in decreased bone formation and enhanced bone resorption leading to accelerated osteoporosis. Drugs such as aluminium and anticonvulsants impair mineralisation, leading to osteomalacia. Other drugs, such as fluoride, are employed for their known effects on bone, but in excess dosage can be harmful by producing mineralisation defects. Management of these conditions will be discussed in this review.

Kamio A, Kummerow F, Imai H. Degeneration of aortic smooth muscle cells in swine fed excess vitamin D3. Arch Pathol Lab Med 1977; 101: 378.

Kano K, Suda T. Serum 25 (OH) D and 24,25 (OH)2 levels in childhood nephrosis under different therapeutic regimens of steroid administration. Eur J Pediatr 1982 Mar;138(2):162-165.
Abstract: The effect of prednisone therapy on serum levels of 25-hydroxyvitamin D [25(OH)D] and 24,25-dihydroxyvitamin D [24,25(OH)2D] was investigated in 16 children with nephrotic syndrome. These serum levels were significantly lower in patients before prednisone therapy than in age- and season-matched normal subjects. Patients receiving daily prednisone therapy had lower serum levels than those receiving alternate-day prednisone therapy at the time when the total amounts of the steroid administered attained 1,500 or 2,000 mg/m2 of body surface area. Daily doses of 40 mg/m2 of prednisone for 3 days caused a significant decrease in serum 25(OH)D levels. Withdrawal of the steroid for 4 consecutive days was followed by a significant recovery of the serum levels. These results suggest that alternate-day prednisone therapy rather than daily treatment should be used in clinical practice to help maintain normal vitamin D metabolism.

Knodel LC, Talbert RL. Adverse effects of hypolipidaemic drugs. Med Toxicol 1987 Jan;2(1):10-32.
Abstract: Cholestyramine, colestipol, clofibrate, gemfibrozil, nicotinic acid (niacin), probucol, neomycin, and dextrothyroxine are the most commonly used drugs in the treatment of hyperlipoproteinaemic disorders. While adverse reaction data are available for all of them, definitive data regarding the frequency and severity of potential adverse effects from well-controlled trials using large numbers of patients (greater than 1000) are available only for cholestyramine, clofibrate, nicotinic acid and dextrothyroxine. In adult patients treated with cholestyramine, gastrointestinal complaints, especially constipation, abdominal pain and unpalatability are most frequently observed. Continued administration along with dietary manipulation (e.g. addition of dietary fibre) and/or stool softeners results in diminished complaints during long term therapy. Large doses of cholestyramine (greater than 32 g/day) may be associated with malabsorption of fat-soluble vitamins. Most significantly, osteomalacia and, on rare occasions, haemorrhagic diathesis are reported with cholestyramine impairment of vitamin D and vitamin K absorption, respectively. Paediatric patients have been reported to experience hyperchloraemic metabolic acidosis or gastrointestinal obstruction. Concurrent administration of acidic drugs may result in their reduced bioavailability. Serious adverse reactions to clofibrate will probably limit its role in the future. Of particular concern are ventricular arrhythmias, induction of cholelithiasis and cholecystitis, and the potential for promoting gastrointestinal malignancy which far outweigh the reported benefits in preventing new or recurrent myocardial infarction, cardiovascular death and overall death. Patients with renal disease are particularly prone to myositis, secondary to alterations in protein binding and impaired renal excretion of clofibrate. Drug interactions with coumarin anticoagulants and sulphonylurea compounds may produce bleeding episodes and hypoglycaemia, respectively. Nicotinic acid produces frequent adverse effects, but they are usually not serious, tend to decrease with time, and can be managed easily. Dermal and gastrointestinal reactions are most common. Truncal and facial flushing are reported in 90 to 100% of treated patients in large clinical trials. Significant elevations of liver enzymes, serum glucose, and serum uric acid are occasionally seen with nicotinic acid therapy. Liver enzyme elevations are more common in patients given large dosage increases over short periods of time, and in patients treated with sustained release formulations.

Kovacs CS, Jones G, Yendt ER. Primary hyperparathyroidism masked by antituberculous therapy-induced vitamin D deficiency. Clin Endocrinol (Oxf) 1994 Dec;41(6):831-836.
Abstract: Antituberculous chemotherapy agents, particularly rifampicin and isoniazid, affect vitamin D metabolism and can create biochemical evidence of vitamin D deficiency. Vitamin D deficiency induces a state of resistance to parathyroid hormone. This study sought to explain the temporary resolution of hypercalcaemia and hypercalciuria, during antituberculous chemotherapy with rifampicin and isoniazid, in a subject with a surgically proven parathyroid adenoma and coincidental spinal tuberculosis. Serum ionized calcium, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, plasma parathyroid hormone, and 24-hour urine excretions of calcium, inorganic phosphorus and hydroxyproline were sequentially measured over a 3-year interval that included 18 months of antituberculous chemotherapy. Initial serum ionized calcium was 1.52 mmol/l (normal 1.20-1.35 mmol/l), 24-hour urine calcium excretion was 9.40 mmol/day (normal 1.25 to 7.50 mmol/day) and plasma intact PTH was 9.2 pmol/l (normal 0.0-4.5 pmol/l). During antituberculous chemotherapy the serum ionized calcium and 24-hour urine calcium excretion were normal but the plasma PTH rose to higher levels. Following completion of the chemotherapy, hypercalcaemia and hypercalciuria returned with levels similar to those observed pretreatment. Serum 25-hydroxyvitamin D was low at 6.25 nmol/l (normal 20 to 90 nmol/l) during antituberculous chemotherapy, but was normal before and after. Serum 1,25-dihydroxyvitamin D was normal throughout the 3-year interval. We conclude that the antituberculous chemotherapy induced relative vitamin D deficiency and resistance to parathyroid hormone action, thereby masking the hyperparathyroidism and hypercalcaemia until the chemotherapy was completed.

Kragballe K. Treatment of psoriasis by the topical application of the novel cholecalciferol analogue calcipotriol. Arch Dermatol. 1989 Dec;125(12):1647-1652.
Abstract: Calcipotriol (the synthetic compound MC 903) is a structural analogue of naturally occurring, biologically active calcitriol. Calcipotriol and calcitriol (1,25-dihydroxy vitamin D3) show similar receptor binding and comparable effects on cell differentiation. However, calcipotriol seems to be at least 100 times less potent in its effects on calcium metabolism. In a double-masked study involving 50 patients with psoriasis vulgaris, the efficacy and tolerability of ointments containing various calcipotriol concentrations (25, 50, or 100 micrograms/g) or the vehicle alone were compared in a study involving a right-left, within-patient randomized design. Patients were treated twice daily for 8 weeks. Marked improvement was seen in 40% of the patients treated with the 25-micrograms/g concentration of calcipotriol in 63% of patients treated with the 50-micrograms/g concentration, and in 88% treated with the 100-micrograms/g concentration. No patient treated with placebo had more than slight improvement. Five patients developed facial dermatitis during the study. The serum levels of ionized calcium were unchanged. This study demonstrates that calcipotriol ointment provides an effective and well-tolerated treatment of psoriasis vulgaris.

Kummerow FA, Cho BH, Huang WY, Imai H, Kamio A, Deutsch MJ, Hooper WM. Additive risk factors in atherosclerosis. Am J Clin Nutr. 1976 May;29(5):579-584.
Abstract: The tissues of human subjects assayed for a higher level of vitamin D than the tissues of 6-month-old swine which had been fed a commercial ration containing 14 times more vitamin D3 than the National Research Council recommended requirement for growing swine. Bioassays of commercial livestock feeds indicate much higher vitamin D contents than the National Research Council recommendation. High levels of vitamin D activity are demonstrable in tissues from the animals on such livestock feeds. The grossly normal areas of the aorta of weanling swine fed 100,000 IU of vitamin D3/pound of basal ration during the initial 6 weeks had a higher frequency of degenerated smooth muscle cells than the grossly normal areas of the aorta of swine fed the commercial ration, or 7.43+/-0.45 and 5.60+/-0.27/100 cells, respectively, at the age of 3 months. Tbe addition of 13 pounds of hydrogenated fat and 200 g of cholesterol/100 pounds of the commercial ration further increased the frequency of degenerated smooth muscle cells by 0.53 (P less than 0.05) or to 7.96 +/- 0.39/100 cells in the grossly normal areas of the aorta of weanling swine fed this fat-supplemented ration to 3 months of age.

Labriji-Mestaghanmi H, Billaudel B, Garnier PE, Malaisse WJ, Sutter BC . Vitamin D and pancreatic islet function. I. Time course for changes in insulin secretion and content during vitamin D deprivation and repletion. J Endocrinol Invest. 1988 Sep;11(8):577-584.

Labriji-Mestaghanmi H, Billaudel B, Garnier PE, Sutter BCJ. Vitamin D and pancreatic islet function. 2. Time course for changes in insulin secretion and content during vitamin D deprivation and repletion. J Endocrine Invest 1988;11:584-587.

Lems WF, Van Veen GJ, Gerrits MI, Jacobs JW, Houben HH, Van Rijn HJ, Bijlsma JW. Effect of low-dose prednisone (with calcium and calcitriol supplementation) on calcium and bone metabolism in healthy volunteers. Br J Rheumatol 1998 Jan;37(1):27-33.
Abstract: The administration of moderate to high doses of corticosteroids is associated with bone loss. This probably results from the uncoupling of bone formation (decreased) and bone resorption (unchanged or increased). We examined the effect of low-dose (10 mg/day) prednisone (LDP) and the possible mitigating effects of calcium and 1.25 (OH)2 vitamin D (calcitriol) on calcium and bone metabolism in eight healthy, young male volunteers. The study consisted of four observation periods: in the first period, LDP was prescribed during 1 week; in the second, third and fourth periods, calcium (500 mg/day), calcitriol (0.5 micrograms b.i.d.) and calcium in combination with calcitriol, respectively, were added to LDP. Bone formation was measured by means of serum osteocalcin, carboxy-terminal propeptide of type 1 procollagen (P1CP) and alkaline phosphatase, bone resorption by means of urinary excretion of calcium, hydroxyproline, (free and total) pyridinoline, (free and total) deoxypyridinoline and serum carboxy-terminal cross-linked telopeptide of type 1 collagen (1CTP). Dietary calcium and sodium intake were maintained at a stable level during the entire study period. Treatment with LDP led to a decrease in osteocalcin, P1CP and alkaline phosphatase (all P < 0.01). Urinary excretion of pyridinolines, hydroxyproline and serum 1CTP did not increase, but remained unchanged or slightly reduced (P < 0.05), depending on the time of measurement and the marker of bone resorption. Parathyroid hormone (PTH) (insignificantly) increased during LDP (+19%) and LDP plus calcium (+14%), but decreased during supplementation with calcitriol (-16%) and calcium/calcitriol (-44%; P < 0.01). Urinary excretion of calcium increased during treatment with LDP and calcitriol (P < 0.05) and calcium/calcitriol (P < 0.05). It is concluded that LDP has a negative effect on bone metabolism, since bone formation decreased while bone resorption remained unchanged or decreased slightly. The increase in PTH during LDP could be prevented by calcitriol combined with calcium supplementation.

Lind L, Skarfors E, Berglund L, Lithell H, Ljunghall S. Serum calcium: A new, independent prospective risk factor for myocardial infarction in middle-aged men followed for 18 years. J Clin Epidemio 1997 Aug;50(8):967-973.
Abstract: BACKGROUND: Primary hyperparathyroidism (HPT) is a disease characterized by hypercalcemia, and associated with an increased mortality in cardiovascular diseases. However, serum calcium levels within the normal range have not been evaluated as a prospective cardiovascular risk factor. METHODS: A cohort of males aged 50 (n = 2183) were investigated in 1970-1973 for serum calcium and known cardiovascular risk factors. They were then followed up over the next 18 years. RESULTS: During the follow-up period, 180 subjects experienced a myocardial infarction (MI). The serum calcium levels were significantly elevated at the baseline (2.37 +/- 0.09 SD versus 2.35 +/- 0.09 mmol/l, p < 0.03) in the subjects who developed a MI when compared with the rest of the cohort. Also blood pressure, body mass index (BMI), fasting insulin, serum cholesterol, serum triglycerides, and the atherogenic index were significantly elevated in the MI group (p < 0.01), while HDL-cholesterol was lower at the baseline investigation (p < 0.01). Cox's proportional hazard analysis showed that only serum calcium (p < 0.01), BMI (p < 0.0003), diastolic blood pressure (p < 0.0009), and the atherogenic index (p < 0.002) were significantly independent risk factors for MI. The range of serum calcium levels from the mean value, -2 SDs to the mean value +2 SDs corresponds to a variation in estimated risk for MI ranging from 0.06 to 0.15. CONCLUSIONS: Serum calcium was found to be an independent, prospective risk factor for MI in middle-aged males suggesting a role for extracellular calcium levels in the atherosclerotic process.

Livingston S. Long-term anticonvulsant therapy and vitamin D metabolism. JAMA 1983;249:939.

Lund B, Andersen RB, Friis T, Hjorth L, Jorgensen FS, Norman AW, Sorensen OH. Effect of 1alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on intestine and bone in glucocorticoid-treated patients. Clin Endocrinol (Oxf) 1977 Dec;7 Suppl:177s-181s.
Abstract: The effect of 1alpha-hydroxyvitamin D3 (1alpha-OHD3) and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on the intestinal calcium absorption was studied in twenty patients with rheumatoid arthritis treated with prednisone at daily doses of 5--15 mg for 1/2--20 years. The fractional calcium absorption, measured before and after the treatment with the vitamin D compounds, increased in nineteen of the twenty patients. This was, however, accompanied by marked rises in the urinary calcium excretion. There was no correlation between the fractional calcium absorption and the duration of the prednisone treatment or the doses given.

Majerus PW, Broze GJ Jr, Miletich JP, Tollefsen DM. Anticoagulant, thrombolytic, and antiplatelet drugs. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York: McGraw-Hill 1996, 1346.

Macallan DC, Maxwell JD, Eastwood JB. Osteomalacia should be sought and treated before withdrawal of anticonvulsant therapy in UK Asians. Postgrad Med J 1992 Feb;68(796):134-136.
Abstract: Individuals from the Asian sub-continent in the United Kingdom are at particular risk of developing osteomalacia. We report a Gujarati woman who developed osteomalacia whilst taking anticonvulsant drugs; withdrawal of anticonvulsant therapy was followed by a seizure complicated by femoral neck fracture. In patients with other risk factors for osteomalacia, as is the case for Asians living in Britain, anticonvulsant drugs should not be reduced or withdrawn until osteomalacia, which puts the skeleton at increased risk of fracture, and its associated hypocalcaemia, which reduces seizure threshold, have been sought and adequately treated.

Mimaki T, Walson PD, Haussler MR. Anticonvulsant therapy and vitamin D metabolism: evidence for different mechanisms for phenytoin and phenobarbital. Pediatr Pharmacol (New York) 1980;1(2):105-112.
Abstract: Combined therapy of epileptic children with phenobarbital (PB) and phenytoin (DPH) significantly decreased serum 25-hydroxyvitamin D (25-OH-D) levels, whereas PB alone significantly increased serum 25-OH-D levels after one to two months of therapy [Sumi et al, 1978]. Studies were conducted in rats to test the hypothesis suggested by the human studies that DPH and PB had different effects on Vitamin D metabolism. Male Wistar rats treated for five days with PB (75 mg/kg/day) had significantly (P less than 0.05) decreased 1,25-dihydroxyvitamin D (1,25-(OH)2D) levels (7.1 +/- 1.6 ng/dl, mean +/- SD) compared to controls (12.0 +/- 4.0 ng/dl) and significantly (P less than 0.005) increased conversion of [3H]-vitamin D into [3H]-25-OH-D and [3H]-24,25-(OH)2D, but no increased conversion into [3H]-25-(OH)2D. Age- and weight-matched rats treated for five days with DPH (75 mg/kg/day), however, had significantly (P less than 0.03) decreased 25-OH-D levels (41.9 +/- 5.7 ng/ml) compared to controls (52.4 +/- 4.4 ng/ml) and significantly (P less than 0.01) increased conversion into [3H]-1,25-(OH)2D. These results are consistent with clinical data, which suggest that different alterations in vitamin D metabolism occur after short-term DPH versus PB therapy.

Morcos MM, Gabr AA, Samuel S, Kamel M, el Baz M, el Beshry M, Michail RR. Vitamin D administration to tuberculous children and its value. Boll Chim Farm 1998 May;137(5):157-164.
Abstract: Our study was done to assess the value of administration of vitamin D to tuberculous children. The study included twenty four newly diagnosed tuberculous children; eleven males and thirteen females. Their age ranged from one and half to thirteen years. Thirteen patients were extra thoracic type of T.B., while only seven were intrathoracic and the rest were mixed. They were randomly divided into two Groups according to the treatment administered: Group A patients were given Rifampicin, Isoniazid and Streptomycin. Group B received in addition vitamin D. After eight weeks therapy, the patients of each group were evaluated regarding clinical, laboratory, and radiological improvement. Vitamin D level is raised after treatment in both Groups A and B, but this rise is not significant. It also showed insignificant difference between the two groups. Vitamin D level showed very high significant decrease in tuberculous children than matched healthy controls (non tuberculous children). Calcium was significantly elevated after treatment in Group A whereas no significant change was detected in Group B. Phosphorous was highly significantly elevated after treatment in Group A, whereas in Group B it is just significantly elevated. Alkaline phosphatase level in both groups A and B were slightly decreased after treatment. However, this decrease was not significant. Clinical improvement was more evident in Group B patients (those taking vitamin D) as compared to Group A patients. The same was noted with X-ray and Sonographic findings. We concluded that vitamin D therapy may be of great value in addition to antituberculous drugs in the treatment of tuberculous children, and its use is highly recommended.

Nelson-Piercy C. Heparin-induced osteoporosis in pregnancy. Lupus 1997;6(6):500-504. (Review)

Nesbitt LT Jr. Minimizing complications from systemic glucocorticosteroid use. Dermatol Clin 1995 Oct;13(4):925-939. (Review)
Abstract: For proper use of systemic GCS, a basic knowledge of the normal HPA axis, as well as knowledge of the pharmacology, clinical usage guidelines, and adverse reactions of these agents is imperative. Both short-term (acute) and long-term side effects should be well known by the physician. The pros and cons of oral and parenteral therapy for various disorders and in various situations should be recognized. For long-term therapy, an intermediate-acting agent such as prednisone in single, early morning doses is most commonly used to minimize suppression of the HPA axis. Alternate-morning doses produce even less suppression if the disease process will respond. A through patient history, including general medical history and medications the patient is taking, is important to anticipate any potential problems. Weight and blood pressure should be checked initially and every 1 to 3 months thereafter. Blood glucose, electrolytes, and lipid studies, including triglycerides, should be done approximately every 6 months. An ophthalmology examination should be performed every year, and stool examination for occult blood and chest radiography can be obtained as indicated. Bone density studies might be necessary in patients who are at high risk for osteoporosis. Specific acute situations may dictate other studies. The patient on long-term GCS should be kept as active as possible, as mild-to-moderate exercise helps prevent certain side effects, such as osteoporosis. The dose of oral GCS is best given with food to prevent gastrointestinal irritation, and agents to decrease gastric acidity might be needed in certain situations. Exposure to infections should be prevented, where possible, and treatment initiated at the first sign of systemic or cutaneous infection. Pain should be evaluated early, especially abdominal pain or bone pain; MRI is indicated if aseptic necrosis of bone is suspected. Both trauma and severe sun exposure should be avoided. Consultation with other specialists is strongly recommended when the situation dictates. Diet is one of the most important strategies to minimize side effects from long-term GCS therapy. Vegetable protein should be increased in the diet, and fats and carbohydrates limited. Adequate calcium is imperative, and calcium supplementation is recommended for high-risk osteoporosis patients. Small amounts of vitamin D may be necessary to increase absorption of calcium. Restriction of sodium is also important, as is maintainance of dietary potassium. Supplemental potassium may be necessary in some patients, and a thiazide diuretic might be useful in patients with hypertension, edema, or osteoporosis. Vitamin C can be given to promote wound healing. A good doctor-patient relationship is important in managing the patient on long-term GCS. The patient must return for regular visits and be encouraged to promptly report any adverse reactions to the physician. If these criteria are maintained and the strategies noted previously are followed, problems from long-term therapy with GCS will be minimized.

Nuti R, Vattimo A, Turchetti V, Righi G. 25-Hydroxycholecalciferol as an antagonist of adverse corticosteroid effects on phosphate and calcium metabolism in man. J Endocrinol Invest 1984 Oct;7(5):445-448.
Abstract: The present study was performed in 30 patients who needed steroid therapy: courses of triamcinolone or DTM 8-15 given orally lasted 30 days. In 15 of these patients glucoactive corticosteroids were administered in combination with 5 micrograms/day of 25OH-vitamin D3 (25OHD3). 47Calcium oral test and 99mTc-MDP kinetics, as an index of bone turnover, were performed at the beginning of the therapy and after 30 days. At the end of treatment a significant improvement of intestinal radiocalcium transport together with a decrease in bone turnover in the group of patients treated with 25OHD3 was observed. As it concerns plasma calcium level, inorganic phosphate, the urinary excretion of calcium, phosphate and hydroxyproline no significant difference between the two groups examined were noticed. These results indicate that the adverse effects of glucoactive corticosteroids on intestinal calcium transport and bone turnover may be counteracted by the combined administration of physiological doses of 25OHD3.

O'Regan S, Chesney RW, Hamstra A, Eisman JA, O'Gorman AM, Deluca HF. Reduced serum 1,25-(OH)2 vitamin D3 levels in prednisone-treated adolescents with systemic lupus erythematosus. Acta Paediatr Scand 1979 Jan;68(1):109-111.
Abstract: The serum levels of 1,25-(OH)2 vitamin D3 were assayed in samples from 12 adolescent patients with SLE. Subnormal levels were observed in 7 of these 12 patients. Low levels of the metabolically active polar metabolite of vitamin D3 may contribute to the development of osteopenia observed in this disease. The cumulative effects of the osteoporotic and anti vitamin D effects of long term steroid therapy in children with SLE may require the cautious administration of supplemental vitamin D.

Palmieri GM, Thompson JS, Eliel LP. Modifications of plasma magnesium by thyrocalcitonin, parathyroid extract and cortisone. Endocrinology 1969 Jun;84(6):1509-1511.

Pluskiewicz W, Nowakowska J. Bone status after long-term anticonvulsant therapy in epileptic patients: evaluation using quantitative ultrasound of calcaneus and phalanges. Ultrasound Med Biol 1997;23(4):553-558.
Abstract: The bone status of 25 epileptic female patients on long-term (mean 19 y) anticonvulsant therapy was investigated using quantitative ultrasound of the calcaneus (Lunar Achilles) and phalanges (Igea DBM Sonic 1200). Comparisons were made with a control group of 43 normal healthy women. Radiogrammetric measurements of the second metacarpal bone were also made in the epileptic patients. While all of the ultrasonic parameters were reduced in the epileptic group, differences only achieved statistical significance for speed of sound (SOS) at the phalanges. Phalangeal SOS correlated significantly with cortical thickness of the second metacarpal bone (r = 0.44, p < 0.05). The data suggest that long-term anticonvulsant therapy is associated with significant cortical bone loss. Quantitative ultrasound may have a role in monitoring bone loss in epileptic patients and in guiding suitable preventive therapy.

Pronsky Z. Powers and Moore's Food-Medications Interactions. Ninth Edition. Food-Medication Interactions. Pottstown, PA, 1991.

Reid IR, Ibbertson HK. Calcium supplements in the prevention of steroid-induced osteoporosis. Am J Clin Nutr. 1986 Aug;44(2):287-290.
Abstract: The long-term use of glucocorticoid drugs frequently results in the development of osteoporosis. To assess the value of calcium supplementation in preventing this loss of bone, the metabolic effects of administering 1 g of elemental calcium/day have been studied in 13 steroid-treated patients. After 2 mo, the fasting urine hydroxyproline-creatinine ratio decreased from 27.1 +/- 2.5 (SEM) to 21.8 +/- 2.4 (p less than 0.001) and there was an increase in fasting urine-calcium excretion (p less than 0.05). Serum alkaline phosphatase and osteocalcin showed no change. We concluded that calcium supplementation suppresses bone resorption without detectable suppression of indices of bone formation and is, therefore, likely to result in increased bone mass. The safety and low cost of calcium make it a very suitable prophylactic agent in glucocorticoid-treated patients.

Reid IR, Ibbertson HK. Corticosteroids and osteoporosis. Aust N Z J Med. 1987 Dec;17(6):611-612. (Letter)

Ringe JD, Becker K. [Osteoporosis caused by long term heparin therapy]. Med Monatsschr Pharm 1985 Mar;8(3):80-83. [Article in German]

Ringe JD, Keller A. [Risk of osteoporosis in long-term heparin therapy of thromboembolic diseases in pregnancy: attempted prevention with ossein-hydroxyapatite]. Geburtshilfe Frauenheilkd 1992 Jul;52(7):426-429. [Article in German] Abstract: Generalized idiopathic osteoporosis and transient osteoporosis of the hip are both rare complications of pregnancy. More frequently, long-term heparin administration to treat deep thrombosis in the legs or pelvis may lead to substantial decreases in bone mass and consequently increased risk of osteoporosis. Therapeutic studies with the aim to counteract the osteoporosis inducing effect of heparins, have not been published to date. In the special situation of pregnancy, most medications used for osteoporosis are contraindicated. In our open randomised study, 9 women on heparin-treatment received daily 6.46 g of the bone preparation OHC (ossein-hydroxyapatite-compound) over a period of 6 months and were compared to 11 women without bone protective treatment. In the OHC-group, good compliance was observed with no side effects and reduced back pain. Bone mass did not change significantly, whilst it dropped significantly statistically in the controls.

Roe DA. Diet and Drug Interactions. New York: Van Nostrand Reinhold, 1989.

Roe DA. Drug-induced Nutritional Deficiencies. 2nd ed. Westport, CT: Avi Publishing, 1985: 158-159.

Roe DA. Risk factors in drug-induced nutritional deficiencies. In: Roe DA, Campbell T, eds. Drugs and Nutrients: The Interactive Effects. New York: Marcel Decker, 1984: 505-523.

Rude RK, Gruber HE, Oldham SB. Cortisone-induced osteoporosis: effects on bone adenylate cyclase. Miner Electrolyte Metab 1993;19(2):71-77.

Rupp WM, McCarthy HB, Rohde TD, Blackshear PJ, Goldenberg FJ, Buchwald H. Risk of osteoporosis in patients treated with long-term intravenous heparin therapy. Curr Surg 1982 Nov;39(6):419-422.

Russell RM, Golner BB, Krasinski SD, Sadowski JA, Suter PM, Braun CL Effect of antacid and H2 receptor antagonists on the intestinal absorption of folic acid. J Lab Clin Med 1988 Oct;112(4):458-463.
Abstract: Intestinal folic acid transport is a saturable process with a pH optimum of 5.5 to 6.0. Because of the possible effects of antacids and acid-lowering drugs on the pH of the proximal small intestine, the influence of these drugs on folic acid absorption was studied by using tritium-labeled pteroylmonoglutamic acid (PGA) in 30 subjects (21 women, nine men) of 56 to 89 years of age. Both cimetidine and an antacid containing aluminum and magnesium hydroxide reduced folate absorption from a liquid formula meal (p less than 0.01, p less than 0.001, respectively). Although ranitidine also caused a fall in folic acid absorption from the liquid meal, the change was not statistically significantly different from when PGA was given with the meal alone. Both histamine receptor antagonists tended to maintain a high intraluminal pH in the proximal small intestine after meals, which in part could explain the inhibition of folate absorption. However, neither drug was found to chemically interact with folic acid, and neither drug inhibited the dihydrofolate reductase. The antacid was found to precipitate folic acid at a pH of greater than 4.0, thus removing it from the aqueous phase. This appears to be the explanation for the lowered folate absorption in the presence of antacid. Although the effects of these drugs on reducing folic acid absorption were relatively small, such reductions could become clinically significant in chronic antacid or H2 receptor antagonist use or intensive antacid or H2 receptor antagonist use by individuals eating diets that are marginal in folate content.

Schrogie JJ. Coagulopathy and fat soluble drugs. JAMA 1975 Apr 7;232(1):19. (Letter)

Scragg R, Khaw K-T, Murphy S. Effect of winter oral vitamin D3 supplementation on cardiovascular risk factors in elderly adults. Eur J Clin Nutr 1995;49:640-646.

Seligmann H, Halkin H, Rauchfleisch S, Kaufmann N, Motro M, Vered Z, Ezra D. Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study. Am J Med 1991 Aug;91(2):151-155.
Abstract: PURPOSE: To test the hypothesis that long-term furosemide therapy in patients with congestive heart failure (CHF) is associated with clinically significant thiamine deficiency via urinary loss. DESIGN: (1) Biochemical evaluation of thiamine status in hospitalized patients with CHF treated with long-term furosemide and in age-matched control patients. (2) Uncontrolled trial of the effect of intravenous thiamine on cardiac performance in a subset of six patients with CHF. SETTING: General medical ward of a teaching community hospital. PATIENTS: Twenty-three patients with chronic CHF receiving furosemide, and 16 age-matched control patients without heart failure and not taking diuretics. Daily furosemide doses were 80 to 240 mg, and duration of furosemide therapy was 3 to 14 months. Patients with identifiable causes of inadequate thiamine intake, absorption, or utilization or increased metabolic requirements were excluded. INTERVENTION: A 7-day course of intravenous thiamine, 100 mg twice daily, in six consenting patients with CHF. RESULTS: A high thiamine pyrophosphate effect (TPPE), indicating thiamine deficiency, was found in 21 of 23 furosemide-treated patients and in two of 16 controls (p less than 0.001). The mean (+/- SE) TPPE (normal: 0% to 15%) in furosemide-treated and control patients was 27.7 +/- 2.5% and 7.1 +/- 1.6%, respectively (p less than 0.001). Despite the high TPPE, the mean (+/- SE) urinary thiamine excretion in the furosemide-treated patients (n = 18) was inappropriately high (defined as greater than 130 micrograms/g creatinine), 410 +/- 95 micrograms/g creatinine, even in comparison with that in the controls (n = 14): 236 +/- 69 micrograms/g creatinine. In six patients treated with intravenous thiamine, the elevated TPPE decreased to normal, from a mean (+/- SE) of 27.0 +/- 3.8% to 4.5 +/- 1.3% (p less than 0.001), indicating normal thiamine utilization capacity. Left ventricular ejection fraction increased in four of five of these patients studied by echocardiography. CONCLUSIONS: These preliminary findings suggest that long-term furosemide therapy may be associated with clinically significant thiamine deficiency due to urinary loss and contribute to impaired cardiac performance in patients with CHF. This deficit may be prevented or corrected by appropriate thiamine supplements.

Stockey IH. Drug Interactions, 4th Edition, London: Pharmaceutical Press, 1996.

Tam CS, Wilson DR, Hitchman AJ, Harrison JE. Protective effect on vitamin D2 on bone apposition from the inhibitory action of hydrocortisone in rats.Calcif Tissue Int 1981;33(2):167-172.

Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS. Hypovitaminosis D in medical inpatients. N Engl J Med 1998 Mar 19;338(12):777-783.
Abstract: BACKGROUND: Vitamin D deficiency is a major risk factor for bone loss and fracture. Although hypovitaminosis D has been detected frequently in elderly and housebound people, the prevalence of vitamin D deficiency among patients hospitalized on a general medical service is unknown. METHODS: We assessed vitamin D intake, ultraviolet-light exposure, and risk factors for hypovitaminosis D and measured serum 25-hydroxyvitamin D, parathyroid hormone, and ionized calcium in 290 consecutive patients on a general medical ward. RESULTS: A total of 164 patients (57 percent) were considered vitamin D-deficient (serum concentration of 25-hydroxyvitamin D, < or = 15 ng per milliliter), of whom 65 (22 percent) were considered severely vitamin D-deficient (serum concentration of 25-hydroxyvitamin D, <8 ng per milliliter). Serum 25-hydroxyvitamin D concentrations were related inversely to parathyroid hormone concentrations. Lower vitamin D intake, less exposure to ultraviolet light, anticonvulsant-drug therapy, renal dialysis, nephrotic syndrome, hypertension, diabetes mellitus, winter season, higher serum concentrations of parathyroid hormone and alkaline phosphatase, and lower serum concentrations of ionized calcium and albumin were significant univariate predictors of hypovitaminosis D. Sixty-nine percent of the patients who consumed less than the recommended daily allowance of vitamin D and 43 percent of the patients with vitamin D intakes above the recommended daily allowance were vitamin D-deficient. Inadequate vitamin D intake, winter season, and housebound status were independent predictors of hypovitaminosis D in a multivariate model. In a subgroup of 77 patients less than 65 years of age without known risk factors for hypovitaminosis D, the prevalence of vitamin D deficiency was 42 percent. CONCLUSIONS: Hypovitaminosis D is common in general medical inpatients, including those with vitamin D intakes exceeding the recommended daily allowance and those without apparent risk factors for vitamin D deficiency.

Threlkeld DS, ed. Blood Modifiers, Anticoagulants, Heparin. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Jun 1997.

Threlkeld DS, ed. Diuretics and Cardiovasculars, Calcium Channel Blocking Agents. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Nov 1992.

Threlkeld DS, ed. Hormones, Adrenal Cortical Steroids, Glucocorticoids. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Apr 1991.

Tjellesen L, Hummer L, Christiansen C, Rodbro P. Different metabolism of vitamin D2/D3 in epileptic patients treated with phenobarbitone/phenytoin. Bone 1986;7(5):337-342.
Abstract: Serum concentrations of vitamin D metabolites were measured before and during treatment with either vitamin D2 or vitamin D3, 4000 IU per day for 24 weeks, in 22 epileptic outpatients receiving phenobarbitone/phenytoin. The serum concentration of total 1,25(OH)2D did not change during the treatment period in any of the treatment groups. On the other hand, in the vitamin D2 group, serum 25(OH)D2, total 25(OH)D, and 24,25(OH)2D increased significantly during the trial, whereas serum concentrations of the vitamin D3 metabolites were unchanged. In the vitamin D3 group, serum concentrations of the vitamin D3 metabolites increased significantly, whereas the vitamin D3 metabolite levels remained unchanged. However, vitamin D3 treatment resulted in a 2-4-fold greater increase in serum concentrations compared to vitamin D2 treatment. Treatment with vitamin D2 and vitamin D3 in the same dose in IU results in considerably different serum concentrations of the vitamin D metabolites.

Tomita S, Ohnishi J, Nakano M, Ichikawa Y. The effects of anticonvulsant drugs on vitamin D3-activating cytochrome P-450-linked monooxygenase systems. J Steroid Biochem Mol Biol 1991 Oct;39(4A):479-485.
Abstract: The effects of two anticonvulsant drugs, phenytoin and sodium valproate, on the bioactivation of vitamin D3 have been studied with respect to the microsomal and mitochondrial cytochrome P-450-linked monooxygenase systems that contribute to 25-hydroxylation of vitamin D3 in rabbit liver, and the mitochondrial cytochrome P-450-linked monooxygenase system that catalyzes 1 alpha-hydroxylation of 25-hydroxyvitamin D3 in rabbit kidney. These anticonvulsant drugs were found to inhibit the 25-hydroxylase activity on vitamin D3 in liver microsomes and mitochondria, respectively, but not to inhibit the 1 alpha-hydroxylation of 25-hydroxyvitamin D3, even over a wide concentration range. Moreover, the activities of the components of the cytochrome P-450-linked monooxygenase systems: NADPH-cytochrome P-450 reductase, NADPH-ferredoxin reductase and ferredoxin, were never inhibited by these drugs. It is possible that the inhibition of bioactivation of vitamin D3 by these anticonvulsant drugs causes rickets and osteomalacia, and the site of inhibition is expected to be the cytochrome P-450 mediated reactions in liver mitochondria.

Tonstad S, Sivertsen M, Aksnes L, Ose L. Low dose colestipol in adolescents with familial hypercholesterolaemia. Arch Dis Child 1996 Feb;74(2):157-160.
Abstract: The effects of orange flavoured colestipol granules, 10 g/day, in 37 boys and 29 girls aged 10-16 years with familial hypercholesterolaemia were examined first in an eight week double blind, placebo controlled protocol, then in open treatment for 44-52 weeks. All patients were on a low fat diet. Low density lipoprotein cholesterol levels were reduced by 19.5% by colestipol v 1.0% by placebo. Levels of serum folate, vitamin E, and carotenoids were reduced in the colestipol group, but not the vitamin E/cholesterol and carotenoid/cholesterol ratios or serum concentrations of vitamins A and D. After one year of colestipol, two thirds of the participants remained in the study, of whom half took > or = 80% of the prescribed dose. Those who took > or = 80% of the dose had a greater decrease in serum 25-hydroxyvitamin D levels than those who took < 80%. No adverse effects on weight gain or linear growth velocity were observed. Although low dose colestipol effectively reduces low density lipoprotein cholesterol levels, only a minority of adolescents adhered to the new formulation for one year. Folate and possibly vitamin D supplementation is recommended.

Toppet M, Vainsel M, Vertongen F, Fuss M, Cantraine F. [Sequential development of vitamin D metabolites under isoniazid and rifampicin therapy]. Arch Fr Pediatr 1988 Feb;45(2):145-148. [Article in French]
Abstract: A sequential study of 25-hydroxy vitamin D (25-OH-D), 1.25 dihydroxy vitamin D [1.25 (OH)2-D], PTH, alkaline phosphatase and gammaglutamyl transpeptidase (gamma GT) was undertaken in a series of 46 children with asymptomatic tuberculosis treated by isoniazid (INH) alone or associated with rifampin (RMP). These parameters were measured before treatment, 1 month, 3 months after the onset and at the end of treatment (6 months). In order to reduce the influence of the time of the year on the 25-OH-D levels, 22 patients were selected for whom the whole treatment took place between October and May of the following year. In this group, 13 children were treated by INH and RMP, 9 by INH alone. A statistically significant decrease in 25-OH-D levels could be demonstrated after 3 months of treatment in 13 patients under INH and RMP as well as a significant increase in alkaline phosphatase and gamma GT levels. In 9 patients given INH alone, 1.25 (OH)2-D levels decreased after 3 months without significant changes in 25-OH-D, alkaline phosphatase or gamma GT levels. These results emphasize the need for regular biochemical supervision, even if no sign of rickets is observed in these patients.
is observed in these patients.

Trovato A, Nuhlicek DN, Midtling JE. Drug-nutrient interactions. Am Fam Physician 1991 Nov;44(5):1651-1658.(Review)

Tsang RC, Roginsky MS, Mellies MJ, Glueck CJ. Plasma 25-hydroxy-vitamin D in familial hypercholesterolemic children receiving colestipol resin. Pediatr Res. 1978 Oct;12(10):980-982.

Turnquist J, Ornoy A, Eini D, Schwartz Z. Effects of 1 alpha(OH)-vitamin D3 and 24,25(OH)2-vitamin D3 on long bones of glucocorticoid-treated rats. Acta Anat (Basel) 1992;145(1):61-67.

USDA: Composition of Foods. USDA Handbook #8 Washington DC, ARS, USDA, 1976-1986.

Watkins DW, Khalafi R, Cassidy MM, Vahouny GV. Alterations in calcium, magnesium, iron, and zinc metabolism by dietary cholestyramine. Dig Dis Sci 1985 May;30(5):477-482.
Abstract: Cholestyramine is an effective drug for the reduction of plasma cholesterol because of its ability to sequester intestinal bile acids. Since metabolic alterations, including diminished intestinal absorption of vitamin D and osteomalacia have been reported with long-term use of this resin, the influence of cholestyramine on dietary balance of four mineral elements has been investigated. Wistar-strain rats were fed either a 2% cholestyramine or control diet for one month. Dietary intakes and fecal and urinary excretions of calcium, magnesium, iron, and zinc were determined using atomic absorption spectrophotometry during three, 3-day balance periods. Cholestyramine-fed rats had a net negative balance for calcium and a lower net positive balance for magnesium, iron, and zinc than the controls. Other effects of cholestyramine were an increased urinary excretion of calcium and magnesium, a decreased urinary zinc, and an alkalinization of urine. Blood and tissue cation content was unchanged except for a reduction in serum magnesium with resin feeding. Alterations in calcium, magnesium, and zinc metabolism might be explained by inadequate vitamin D absorption from the intestine followed by an increased secretion of parathyroid hormone. A diminished iron absorption due to resin binding could account for the reported disturbance in iron balance.

Weisman Y, Schen RJ, Eisenberg Z, Edelstein S, Harell A. Inadequate status and impaired metabolism of vitamin D in the elderly. Isr J Med Sci 1981 Jan;17(1):19-21.
Abstract: The mean serum concentrations of 25-hydroxyvitamin D and of 24,25-dihydroxyvitamin D were significantly lower (P less than 0.01) in 82 elderly people than in 30 young control subjects. The levels in 30 elderly people confined to their rooms were 8.0 +/- 0.7 (SE) and 0.54 +/- 0.04 ng/ml, respectively; in 31 active old-age-home residents who spent part of their time outdoors, they were 11.4 +/- 0.8 and 0.82 +/- 0.08 ng/ml, respectively; and in 21 elderly farm workers, 14.6 +/- 1.4 and 0.98 +/- 0.10 ng/ml, respectively. In the young control subjects, the levels were 21.5 +/- 1.4 and 1.91 +/- 0.12 ng/ml, respectively. In addition, an intestinal absorption test with a standard oral dose of 25-hydroxyvitamin D3 showed that the serum 25-hydroxyvitamin D3 responses at 4 and 6 h were considerably depressed in 10 of the 20 elderly subjects in whom the test was performed.

Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997. (Review).

West RJ, Lloyd JK. The effect of cholestyramine on intestinal absorption. Gut. 1975 Feb;16(2):93-98.
Abstract: Cholestyramine in a mean dosage of 0-6 g/kg/day has been given to 18 children with familial hypercholesterolaemia for between one and two and a half years. With prolonged treatment folate deficiency occurred, as evidenced by a fall in the mean serum folate concentration from 7-7 ng/ml before treatment to 4-4 ng/ml for patients on treatment for over one year; a corresponding lowering of red cell folate was also seen. Oral folic acid 5 mg daily overcame this depletion, and should be given to all patients on long-term anion exchange resins. Prothrombin time has remained normal in all patients; there has been a significant decrease in the mean serum concentrations of vitamins A and E and of inorganic phosphorus over the first two years of treatment, although values remain within the normal range. The routine administration of fat-soluble vitamins appears unnecessary but it is prudent to measure prothrombin time and serum vitamins A and E at intervals. In children who were having a normal intake of dietary fat five out of seven tested had faecal fat of over 5 g/day while on cholestyramine. No child has developed diarrhoea, and growth has been normal. The concentrations of serum iron, vitamin B12, plasma calcium, and protein did not change significantly in any patient.


Williams C, Netzloff M, Folkerts L, Vargas A, Garnica A, Frias J. Vitamin D metabolism and anticonvulsant therapy: effect of sunshine on incidence of osteomalacia. Southern Med J 1984 Jul;77(7):834-6, 842.
Abstract: To study the association between anticonvulsant therapy and osteomalacia or rickets, we evaluated 450 epileptic patients receiving anticonvulsants and residing in an institution for the mentally retarded in Florida. Fifty-five of them with increased mean serum alkaline phosphatase and mildly depressed mean serum calcium levels were identified as being at risk for having osteomalacia. None of them, however, had low serum levels of vitamin D (25[OH]D) or radiologic evidence of osteomalacia or rickets. In contrast to reports from northern climates, we found minimal evidence of anticonvulsant-induced bone disease. The study suggests that exposure to sunshine in our patients probably prevented the development of anticonvulsant-induced osteomalacia or rickets.

Wise PH, Hall AJ. Heparin-induced osteopenia in pregnancy. Br Med J 1980 Jul 12;281(6233):110-111.
Abstract: Multiple vertebral compression fractures occurred in a pregnant woman receiving heparin over nine months. This phenomenon may be more common than is clinically recognised and warrants careful re-examination of the indications and method of administration of anti-coagulants during pregnancy.

Yeh JK, Aloia JF, Semla HM. Interrelation of cortisone and 1,25 dihydroxycholecalciferol on intestinal calcium and phosphate absorption. Calcif Tissue Int 1984 Sep;36(5):608-614.
Abstract: The interrelation of glucocorticoids and 1,25 dihydroxycholecalciferol (1,25(OH)2D3) on intestinal calcium and phosphate absorption was investigated. The active and passive transport of calcium and phosphate was evaluated by the in situ intestinal loop technique. Administration of cortisone resulted in a decrease of the luminal fluid and an increase of the luminal calcium and phosphate concentration. Under active transport conditions, administration of cortisone resulted in a decrease of net calcium absorption through two mechanisms: (1) depressed vitamin D-dependent calcium absorption, (2) increased vitamin D-independent calcium backflux. The enhancement of bidirectional phosphate flux by cortisone was independent of 1,25(OH)2D3. An enhancement of water movement by cortisone resulted in an increase of luminal calcium and phosphate concentration which favors the passive diffusion of these ions. Enhanced calcium diffusion by cortisone compensates for the inhibitory effect of cortisone on vitamin D-dependent calcium transport. However, enhanced phosphate diffusion by cortisone is additive to the effect of 1,25(OH)2D3.