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Drugs Aging.  1994 Oct; 5(4) :300-17
Calcitriol. A review of its use in the treatment of postmenopausal osteoporosis & its potential in corticosteroid-induced osteoporosis.

Dechant KL, Goa KL
Adis International Limited, Auckland, New Zealand..


A synthetic form of calcitriol (1,25-dihydroxycholecalciferol; 1,25-dihydroxyvitamin D3), the most physiologically active metabolite of vitamin D, has shown efficacy in the treatment of postmenopausal osteoporosis and promise in corticosteroid-induced osteoporosis. Although results of small studies investigating calcitriol in the treatment of postmenopausal osteoporosis demonstrated that patients with mild to moderate disease who received calcitriol (0.25 microgram twice daily) had a significant 3-fold lower rate of new vertebral fractures after 3 years of treatment, compared with patients receiving elemental calcium 1000 mg/day.  In patients commencing long term treatment with prednisone or prednisolone, calcitriol 0.5 to 1.0 micrograms/day plus calcium 1000 mg/day, administered with or without intranasal calcitonin 400 IU/day, prevented steroid-induced bone loss. Overall, calcitriol is well tolerated.  As shown in clinical studies, at recommended dosages hypercalcaemia is frequent and mild, generally responding to reductions in calcium intake and /or calcitriol dosage.  The narrow ‘therapeutic window’ of  calcitriol requires that its use be adequately supervised, with periodic monitoring of serum calcium and creatinine levels.  However, significant renal toxicity has not been seen in patients with osteoporosis treated with calcitriol in high dosages for several years in comparative and noncomparitive trials.  In conclusions, as with other drugs currently used in the management of patients with osteoporosis, questions remain to be answered regarding the efficacy of calcitriol relative to other agents, and its tolerability in such patients during the very long term.  Nonetheless, at this stage, calcitriol should be considered a useful treatment option in patients with mild to moderate postmenopausal osteoporosis. 

CONCLUSION

Calcitriol the most physiologically active metabolite of vitamin D, has shown efficacy in the treatment of postmenopausal osteoporosis and promise in corticosteroid-induced osteoporosis, a clinical trial in 622 women with postmenopausal osteoporosis demonstrated that patients with mild or moderate disease who received calcitriol (0.25) microgram twice daily) had a significant 3-fold lower rate of new vertebral fractures after 3 years of treatment, compared with patients receiving elemental calcium 1000 mg/day.

 Osteoporosis Int. 2000; 11(1); 43-51 
 Calcium absorption in postmenopausal osteoporosis: benefit of HRT alone, in both malabsorbers and normal absorbers.

Holzherr ML, Retallack RW, Gutteridge DH, Price RI, Faulkner DL, Wilson SG, Will RK, Stewart GO, Stuckey BG, Prince Rl, Criddle RA, Kent GN, Bhagat CI, Dhaliwal SS, Jamrozik K.
Departments of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia.

In a randomized trial involving 71 Postmenopausal osteoporotic women with vertebral compression fractures, radiocalcium absorption studies using the (45) Ca single isotope method (alpha) were performed at baseline and after 8 months of treatment with either continuous combined hormone replacement therapy (HRT, as piperazine estrone sulfate 0.625-0.937 mg daily +/- medroxyprogesterone acetate 2.5 mg daily depending on uterine status) or HRT plus calcitriol 0.25 micro twice daily.  A calcium supplement of 600 mg nocte was given to only those women who had a daily calcium intake less than 1 g per day at baseline, as assessed by recalled dietary intake.  There was a significant decrease [0.74 (+/- 0.35 SD) to 0.58 (+/- 0.22), Dalpha=-0.17 (+/- 0.26), p<0.0005} in alpha at 8 months compared with baseline in the HRT-treated group, but a significant increase [0.68(+/-0.27), Dalpha=baseline +0.16(+/- 0.30), p<0.003] in the HRT –only group.  Although 72 % of the patients had been supplemented with calcium between the first and second studies, separate analyses revealed that the change in calcium intake had not affected the result.  Further breakdown of the groups into baseline ‘normal’ absorbers (alpha>/=0.55) and ‘malabsorbers’ (alpha<0.55) revealed that alpha decreased with HRT plus calcitriol treatment , alpha increased only in the malabsorbers, the normal absorbers in this group remaining unchanged.  In conclusion, our data show that HRT, of the type and dose used in this study, did not produce an increase in absorption efficiency; it was in fact associated with a fall.  Increased absorption efficiency cannot be achieved unless calcitriol is used concurrently, and then only in patients with malabsorption.  Calcitriol also had a significant effect in normal absorbers in that if prevented the decline in alpha seen with HRT alone, and thus should be considered in all patients with post menopausal osteoporosis treated with HRT.
 

CONCLUSION

In conclusion, our data show that HRT, of the type and dose used in this study, did not produce an increase in absorption efficiency; it was in fact associated with a fall.  Increase absorption efficiency cannot be achieved unless calcitriol is used concurrently, should be considered in all patients with postmenopausal treated with HRT.

Ann Intern Med. 1990 Nov 1:113(9): 649-55
 Treatment of postmenopausal osteoporosis with high doses of synthetic calcitriol. A Randomized controlled   study.
 Gallanghar JC, Goldgar D.
 Bone Metabolism Unit,
Creighton University Medical Center, Omaha, NE 68131.
 

Objectives: To study the efficacy of synthetic 1, 25 dihydroxyvitamin D3 (Calcitriol) in the treatment of osteoporosis. DESIGN: Two-year, double-bind, randomized clinical trial. 

Setting: University medical center. Patients: Fifty postmenopausal women with vertebral fractures recruited by referral. Calcium intake was adjusted to 25 mmol/d (1000 mg/d) at baseline. Patients were then randomized to treatment with either calcitriol or placedo.  During the study, calcium intake was reduced to 15 mm/d (600 mg/d) and the dose of calcitriol was adjusted to maintain serum calcium less than2.74 mmol/L (less than 11.0 mg/dl) or urine calcium less than 9.96 mmol/d (less than 400 mg/d). 

Methods: After 2 years, the mean dose of calcitriol in the treated group was 0.62 micrograms/d. Bone mineral density of the spine increased 1.94% with calcitriol therapy and decreased 3.92% with placebo (P=0.001). Total body calcium increased 0.21% with calcitriol therapy and decreased 1.85% with placebo (P=0.004). There were no differences in vertebral fractures rates between the groups. Renal function studies were not statistically different between the groups after 2 years. 

CONCLUSION 

The treatment of postmenopausal osteoporotic women with synthetic calcitriol for 2 years was associated with increased in spine density and total body calcium.  No adverse effects on renal function were seen after long term calcitriol therapy.  The treatment of postmenopausal osteoporotic women with synthetic calcitriol for 2 years was associated with increases in spine density and total body calcium.  No adverse effects on renal function were seen after long-term calcitriol therapy.

Calcif Tissue Int. 2000 Aug: 67(2):122-7
Bone mass and markers of bone and calcium metabolismin postmenopausal women with 1, 25-dihydroxyvitamin D (Calcitriol) for four years. 
Sairanen S, Karkkainen M. Tahtela R. Laitinen K. Makela P. Lamberg-Allardt C. Valimaki MJ. Department of Medicine,
Helsinki University Central Hospital
, Finland.

 To evaluate the long term effect of calcitriol treatment on bone mineral density (BMD) of the femoral neck and lumbar spine and the parameters of calcium and bone metabolism in elderly women, 55 healthy, postmenopausal women, all aged 65 years, were enrolled in the study.  Eighteen started a 4-year supplementation with 0.5 microg of calcitriol daily and 37 served as controls.  Calcium intake of all the subjects was adjusted to 800 mg daily.  In 4 years femoral neck BMD increased by 3.0% in the calcitriol group, but decreased by 1.6% in the control group (P=0.009). The respective changes in lumbar spine BMD were +2.3% and +0.9% (P=0.067). Two years treatment with calcitriol increased intestinal absorption of strontium by 57% (P<0.001), doubled the urinary excretion of calcium (P<0.01), and the marker of bone resorption, serum C-telopeptide of type I collagen (CTx), by 33 % (P=0.05) after 2 years. In two subjects the calcitriol does had to be reduced because of hypercalciuria.  We conclude that calcitriol treatment increases bone mass at the femoral neck and lumbar spine, the increases being maintained for up to 4 years.  The gain in bone mass results from reduced bone turnover which is partly a consequence of the enhanced intestinal absorption of calcium and suppressed serum PTH levels.                                                                       

CONCLUSION

 That calcitriol treatment increases bone mass at the femoral neck and lumbar spine, the increases being maintained for up to 4 years.

J Clin Endocrinol Metab, 2001 Aug; 86(8) : 3618-28
Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss.
Gallaghar JC, Fowler SE, Detter JR,
Sherman SS.
Creighton University Medical Center, St Joseph Hospital, Omaha Nebraska 68131, USA.
JCG@creighton.edu.

 Estrogen deficiency and declining calcium absorption due to reduced calcitriol levels or intestinal resistance to calcitriol, are important factors in the pathogenesis of age-related bone loss.  The main objective of this study was to examine the effect of estrogen and 1,25-dihydroxyvitamin D therapy given individually or in combination on bone loss in elderly women.  Four hundred eighty-nine elderly women with normal bone density for their age, aged 65-77 yr, were entered into a randozed double blind, placebo-controlled trial.  Women were randomized to one of four groups: plus medroxyprogestrone acetate (2.5 mg. Daily) to women with a uterus (estrogen replacement therapy) plus calcitriol, or placebos for 3 yr.  The primary outcome was the change in the bone mineral density of the femoral neck and spine.  In the intent to treat analysis, hormone therapy ( hormone replacement therapy/estrogen replacement therapy) produced a mean (+/- 1SD) increase in bone mineral density of  2.98% (+/-5.45%) at the femoral neck (P<0.0001) and 4.36% (+/-6.42%) at the spine (P<0.001), 4.91% (+/-6.0%) at the spine (P<0.0001), and parallel changes at the total hip and trochanter.  All three treatment groups differed significantly from placebo at the spine and for the hormone replacement therapy/estrogen replacement therapy groups at the femoral neck, spine, total hip and trochanter.  There were no significant differences between combination therapy and hormone replacement therapy/estrogen replacement therapy alone or bone mineral density at any site in the intent to treat analysis. In a secondary analysis of the effect in women who were adherent to treatment, calcitriol had a more significant effect on spine (P=0.003) and total hip bone mineral density (P=0.0017). in summary, hormone replacement therapy/estrogen replacement therapy alone and in combination with calcitriol therapy was highly effective in reducing bone resorption and increasing bone mineral density at the hip and other clinically relevant sites in a group of elderly women, with normal bone density for their age. Calcitriol was effective in increasing spine bone mineral density. In the adherent women, with normal bone density significantly more in the total hip and trochanter than did hormone replacement therapy/estrogen replacement therapy alone. 

CONCLUSION 

Calcitriol was effective in increasing spine bone mineral density.  In the adherent women, combination therapy with hormone replacement therapy/estrogen replacement therapy and calcitriol increased bone mineral density significantly more in the total hip and trochanter than did hormone replacement therapy/estrogen replacement therapy alone. 

 Bone. 1998 Sep: 23(3) 297-302
 Effects of short-term treatment with predisolone and calcitriol on bone and mineral metabolism in normal men.
 Gram J.Junker P.Nielsen HK, Bollerslev J.
 Department of Endocrinology,
Odense University Hospital, Denmark.

 To study the effects of treatment with glucocoticoid and calcitriol on biochemical markers of calcium and bone metabolism, 48 normal male volunteers (aged 21-54 years) were randomized to treatment of 7 days with either  (A) predisolone, 10 mg twice daily, (B) predisolone, 10 mg twice daily, and calcitriol, 1 microg twice daily, (C) calcitriol 1 mg twice daily, or (D) placebo. The study period was 28 days. Renal calcium excretion increased ( mean maximal increase +44.7%, p<0.01) as well as serum parathyroid hormone (PTH)  (Max. –43.1% , p<0.001). Prednisolone administration was followed by prompt declines in markers of bone formation {serum osteocalcin (max. –34.7%, p<0.001) Where as serum bone alkaline phosphatase (bone Ap) remain unchanged. Calcitriol in combination with prednisolone attenuated the decrease in  PICP (max. –8.9%, is not significant), but it had no effect on osteocalcin (max-40.1%, p<0.001), decrease in PICP (max.-8.9%,not significant), but it had no effect on osteocalcin (max,-40.1%,p<0.001), and decreased bone AP (max.-22.2%,p<0.005). Among markers of bone degradation, prednisolone suppressed serum C-terminal telopeptide of type I Collagen (ICTP) (max.-17.2%, ,p<0.001). Calcitriol alone had no effect on resorptive markers.  Extraosseosus matrix synthesis was suppressed by prednisolone evaluated by serum procollagen type III N-terminal propeptide 9max.-30.8%, p<0.001) and was not affected by concomitant treatment with calcitriol or calcitriol alone. In conclusion, short term administration of prenisolone to healthy men leads to fast and protracted suppression of biochemical markers of bone formation and extraosseous connective tissue metabolism.  The effect on bone was partially antagonized by simultaneous calcitriol treatment, and points toward a points toward a potential role of calcitriol in the prevention of steroid induced osteoporosis.

 CONCLUSION

Short-term administration of prednisolone to healthy men leads to fast and protracted suppression of biochemical markers of bone formation and extraosseous connective tissue metabolism. The effect on bone was partially antagonized by simultaneous calcitriol treatment, and points toward a potential role of calcitriol in the prevention of steroid induced osteoporosis.

  STEROID INDUCED OSTEOPOROSIS
 N.Engl J.Med. 1993 Jun 17;328 (24):1747-52
 Prevention of corticosteriod osteoporosis. A comparison of calcium, calcitriol, and calcitonin.
 Sambrook P. Birmingham J, Kelly P, Kempler S, Nguyen T. Pocock N. Eisman J.

 Background: Prolonged corticosteroid therapy increases the risk of ostroporosis and fracture . We studied whether corticosteroid-induced osteoporosis could be prevented by treatment with calcium, calcitriol (1,25-dihydroxyvitamin D3), and calcitonin.

 Methods: One hundred three patients starting long-term corticosteriod therapy were randomly assigned to receive 1000 mg of calcium per day orally and either calcitriol (0.5 to 1.0 microgram per day orally) plus salmon calcitonin (400 IU  per day intranasally), calcitriol plus a placebo nasal spray, or double placebo of one year. Data on treatment efficacy were available for 92 of these patients.  Bone density was measured every four months for two years by photon absorptiometry. These were no significant differences between groups with respect to age, underlying disease, initial bone density, or corticosteriod dose during the first year.

 Result: Calcitriol (Mean dose, 0.6 microgram per day) with or without calcitonin prevented more bone loss from the lumbar spine (mean rates of change, -0.2 and –1.3 percent per year) respectively ) than calcium, alone (-4.3 percent per year, P=0.0035). Bone loss at the femoral neck and distal radius was not significantly affected by any treatment.  In the second year, Lumbar bone loss did not occur in the group given calcium alone (-2.3 percent per year). The Calcitriol group also lost lumbar bone (-3.6 percent per year) but received more corticosteroid in the second year than the other groups.

CONCLUSION
 

Calcitriol and calcium, used prophylactically with or without calcitonin, prevent corticosteroid-induced bone loss in the lumbar spine. 

ROLE OF ZINC IN OSTEOPOROSIS

The Journal of Trace elements in Experimental Medicine 11: 119-135 (1998)
Role of Zinc in Bone Formation and Bone Resorption
Masayoshi Yamaguchi

Laboratory of Endocrinology and Molecular Metabolism, Graduate School of Nutritional Sciences, University of  Schizuoka, Schizuoka City, Japan.

 Zinc is essential for the growth of the human and other animals. Bone growth retardation is a common finding in various conditions associated with zinc deficiency, Suggesting a physiological role of zinc in the growth and mineralization of bone tissue.  Bone zinc content is decreased by development with aging, skeletal unloading and postmenapausal conditions.  Zinc has been demonstrated to have stimulatory effect on bone formation and mineralization; the metal directly activates aminoacyl-tRNA syhthetase in osteoblastic cells and it stimulates cellular protein synthesis. Moreover, zinc inhibits osteoclastic bone resorption by inhibiting osteoclast like cell formation from marrow cells. Zinc may act on the process of bone-resorbing factors induced protein kinase C activation, which is involved in Ca2 signalling in Osteoclastic cells. Zinc plays a role in the preservation of bone mass.
 

CYSTIC FIBROSIS & OSTEOPOROSIS
Osteoporosis Int. 2003 Jun; 14(5) : 442-9, Epub 2003 May 28
 Short term calcitriol administration improves calcium homeostasis in adults with cystic fibrosis.
 Brown SA, Onties DA, Lester GE, Lark RK, Hensler MB, Blackwook AD, Carminiti MJ Backlund DC, Aris Rm, Division of Endocrinology, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill North Carolina 27599, USA. Sue_brown@med.unc.edu

 Clinical Trials

Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis.
 Author
Qiu GX: Gao SN; Giacovelli G: Rovati L: Setnikar I
Address

Peking
Union Medical College Hospital, The Peoples Republic of China.
Source
Arzneimittelforshung, 48(5):469-74 1998 May
Abstract

A double-bind therapeutic investigation was performed on 178 Chinese patients suffering from osteoarthritis of the knee randomized into two groups, one treated for 4 weeks with glucosamine sulfate (GS,CAS 29031-19-4,Viatril-S) at the daily dose of 1,500 mg and the other ibuprofen (IBU, CAS 15687-27-1) at the daily dose of 1,200 mg.Knee pain at rest, at movementand at pressure, knee swelling, improvement and therapeutic utility as well as adverse events and drop-outs were recorded after 2 and 4 weeks of treatment.  The variables were recorded also after 2 seeks of treatment discontinuation in ordr to appreciate ht eremnant therapeutic effect.  Both GS and IBU significantly reduced the syumptoms of osteoarthritis with the trend of Gs to be more effective.  After 2 weeks of drug discontinuation there was  a remnant therapeutic effect in both groups, with the trend to be more pronounced in the GS group.  GS was significantly better tolerated than IBU, as shown by the adverse drug reactions (6% in the patients of the GS group and 16 % in the IBU group—p=0.02) and by the drug-related drop outs (0% of the patients in the GS group and 10 % in IBU group –p=0.0017) The better tolerability of GS is explained by its mode of action., because GS specifically curbs the pathogenic mechanisms of osteoarthritis and does not inhibit the cyclooxygenases as the non-steroidal anti-inflammatory analgesic activities but also with the several adverse reactions due to this not targeted effect.  The present study confirms that GS is a selective drug for osteoarthritis, as effective on the symptoms of the disease as NSAIDS but significantly better tolerated.  For these properties GS seems particularly indicated in the long term treatments needed in osteoarthritis.

 Language
Eng
Unique Identifier
98302160
MESH Headings
Adult: Aged; Antirheumatic Agents AE/*TU: Comparative study: Female: Glucosamine AE/*TU; Human: Ibuprofen AE/*TU; Knee*/PA; Male; Middle Age; Osteoarthritis*DT/PA; Pain Measurement DE.
Publication Type
Clinical Trial; Journal Article; Randomized Controlled Trial
ISSN
0004-4172
Country of Publication

GERMANY

CAS Registry Number
0(Antirheumatic Agents): 15687-27-1 (Ibuprofen): 3416-24-8 (Glucosamine)

numerous double-blind studies have shown GS to produce much better compare to NSAIDS in relieving the pain and inflammation associated with osteoarthritis. E23.24 in one study comparing GS to Ibuprofen, pain scores decrease faster in the first two weeks in the ibuprofen group however by the fourth week the group receiving GS was going significantly better than the ibuprofen group. 

In another large open trial carried out in Portugal , 25 patients receiving 500 mg . oral GS three times a day over a period of approximately 50 days, showed a significant improvement in mobility and reduction in pain.  Overall, 95% of patients achieved benefit from GS. Both doctors and patients rated the GS was going significantly better than the ibuprofen group.
 

In another large open trial carried out in Porugal, 25 patients receiving 500mg. of oral GS three times a day over a period of approximately 50 days, showed a significant improved in mobility and reduction in pain.  Overall, 95% of patients achieved benefit from GS. Both doctors and patients rated the GS  as being significantly better than NSAIDS. NSAIDS tents to offer purely symptoms relief, and as described earlier, may even exacerbate the disease. 

GS appear to address the cause of osteo arthritis by getting to the root of the problem, therefore GS not only relief’s pain but also pain help with the repair of damaged joints this is truly outstanding considering its safety and lack of side effects.  The latest finding of a large, three years European study of the effects of GS where recently presented at The American College of Rheumatology. 26 before and after X-rays of 212 osteoarthritis patients showed that 22% of those taking a daily 1500mg. Supplement of GS had detoriation in their knee joints compare to 38% of patients taking placebo. Over the three pain stiffness and physical function improved in the Glucosamine group but worsened in the placebo group. 

COMPARISON OF GLUCOSAMINE VS PIROXICAM

Symptoms of osteoarthritis.  Two types of studies have been performed , those that compared glucosamine against placebo and those that compared it against standard medications.

A recent double-blind study compared glucosamine sulfate against placebo in 252 people with osteoarthritis of the knee. 14 after 4 weeks, the group that was given glucosamine experienced significantly reduced pain and improved movement, to a greater extent than the improvements seen in the placebo group. 

Another double-blind study followed 329 people who were divided into four groups. One group was given the standard antiarthritis drug piroxicam (Feldene). A second was given glucosamine, a third received both treatments, and the fourth received  placebo only. 15,16 over 90 days, piroxicam and glucosamine proved equally effective at reducing symptoms, interestingly the combination treatment (Piroxicam plus glucosamine) didn’t produce significantly better results than either treatment taken alone. 

After 90 days, treatment was stopped and the participants were followed for an additional 60 days.  The benefits of piroxicam rapidly disappeared, but the benefits of glucosamine lasted for the full 60  days.

 Therapeutic Approaches:

Glucosamine occurs naturally in joint structures, as supplemental glucosamine sulphate. It is currently prized primarily for its efficacy in arthritis conditions , contributing to the reduction of arthritis joint pain and the repair of the joint surfaces. Dr. Bucci classifies it as a nutraceuticals since it occurs naturally but is clinically efficacious. 

To be more specific, beyond the vague generalization of arthritic , glucosamine is indicated for the following tissues:

Synovial Fluids

Muscle Tissues, Tendons and Ligaments
Dehydrated Inter-Vertebral discs
Inflamed discs and sciatica
Degenerated Joints (Osteoarthritis Associated with aging)
Inflamed Joints (Rheumatoid Arthritis)

 Toxicity Factors:

 Glus c               

   

 

 

 
 
     
     
   

Being seventy is not a sin.- Golda, quoted by David Reed, Reader’s digest, July 1971

   
 
                 
   

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