Part of the pathogenesis of Osteoporosis is:
* Poor calcium absorption from the intestine
* Declining renal function due to age

Plain form of vitamin D requires liver and kidney hydroxylations to become activated form of Vitamin D.

One-Alpha® does not require kidney activation but only liver activation.

Therefore, One-Alpha® will correct the state of calcium malabsorption from the intestine and increase the bone mineral density in osteoporosis.
Without the need of kidney activation.

One-Alpha® 0.5μg daily is more effective and easier to control than plain Vit. D.

If the patients dietary intake contains calcium then Calcium supplement is not a must.

Combine:
One-Alpha® μg daily and Calcium
                  OR
use One-Alpha® alone if patient daily calcium supplement is ensured.

There is no Relation and it is like if you want to convert Litres into Kilogrammes.

Bone pain in Osteoporosis is a result of bone resoprtion. Once bone resorption is corrected, bone pain is relieved.

If One-Alpha® is given alone it could be established that bone pain will be relieved with 2-3 months.

Yes,
The fact that One-Alpha® requires a 25 hydroxilation in the liver leads to speculations about its activity in the presence of liver disorders.

"However the clinical efficacy of small doses of One-Alpha® in patients with primary biliary cirrhosis implies that there is no defect in the hydroxylation step even in the presence of severe liver disease". (1), (2)

REFERENCES
1. Compston JE, Crowe JP, Horton LWL
Treatment of osteomalacia associated with primary biliary cirrhosis with oral 1-alpha-hydroxy vitamin D3.
Br Med J 1979; 2: 309

2. Varghese Z et al.
The effect of oral 1-alpha-hydroxyvitamin D3 and 1,25-(OH)2D3 on the intestinal absorption of calcium and phosphate in primary biliary cirrhosis.
Vitamin D Basic Research and its Clinical Application 1979; 1045-1049.
Ed: AW Normal et al. Walter de Gruyter, Berlin.

The only side is Hypercalcaemia and it is avoided by regular monitoring of the patient serum calcium during treatment (every 3 months).

Yes,
Calcitonin will:
* Inhibit bone resorption
* and have a remarkable analgesic effect.

While One-Alpha® will:
* Improve intestinal calcium absorption
* Increase bone mineral content.

Thus a combination of:
"Calcitonin and low doses of 0.5-1μg of 1α(OH)D3 or 0.025-0.5μg 1,25(OH)2D3 will prove to be an effective therapy in the treatment of Osteoporosis". (3)

REFERENCES
3. In: Osteoporosis Eds: G Menczel, et al. Chichester: John Wiley & Sons, 1982: 394-406

Yes,
Estrogen will: delay or prevent bone loss.

But as Calcium malabsorption and impaired Kidney functions are important features of osteoporosis, Estrogen will be of little value.

While One-Alpha® will:
* Improve intestinal calcium absorption
* Increase bone mineral content.

Combine:
One-Alpha® 0.5μg daily and HRT
"A much more pronounced bone sparing effect can be expected when estrogen is administered concomitant with vitamin D3 rather than it is used alone". (4)

REFERENCES
4. I. Gorai et al. A comparative study on effect of Estrogen vs vitamin D on postmenopausal bone loss.
J Bone Miner. Res 1994; 9(Suppl 1): S 327

Plain vitamin D in high doses is effective in healing rickets and osteomalacia, i.e. diseases with severe vitamin D deficiency or resistance. In selected populations of elderly people with low vitamin D levels (vitamin D insufficiency) it will decrease PTH, slightly increase BMD, and thereby reduce the risk of fractures.

In the large number of osteoporotic patients who are replete in vitamin D, no significant effects can be expected from plain vitamin D. Nevertheless, very often calcium plus vitamin D supplements are given just to guarantee an optimal supply.

Also in patients under long-term corticoid therapy it has been shown that calcium plus plain vitamin D alone has no significant effect on BMD [1].

After intestinal absorption alfacalcidol will readily be activated in the liver into 1,25-dihydroxycholecalciferol (= calcitriol), i.e. the plasma level of this active hormone will be augmented inducing effects on calcium absorption, PTH, and bone turnover. This will never occur even with rather high doses of plain vitamin D because the second activation step in the kidney (1α-hydroxylase) is strongly regulated. Alfacalcidol, however, is already 1α-hydroxylated, and activation in the liver will take place quantitatively without registration.

Table 15 summarizes the most important differences between plain vitamin D and the active analogue alfacalcidol.

From a therapeutic point of view plain vitamin D can be used as a nutritional supplement in case of insufficient supply, while alfacalcidol is a specific antiosteoporotic drug.

Table 15      Plain vitamin D or active alfacalcidol ?

Plain vitamin D - Nutriotional substitution	Alfacalcidol - Pharmacological treatment
- Only effective in patients with vitamin D insufficiency - In vitamin D replete patients no further increase of 1,25-(OH)2-D (calcitriol) takes place	- Prodrug for calcitriol, will be activated in the liver and in bone - Resulting increase in active D-hormone will decrease PTH and bone resorption, and increase formation

REFERENCES
1. Ringe JD, Faber H.
Calcium and vitamin D in the prevention and treatment of glucocorticoid-induced osteoporosis.
Clin Exp Rheymatol 2000; 18 Suppl 21: S44-S48

The prodrug alfacalcidol is hydroxylated in the liver to the active D-hormone (see previous question). The different effects of this very potent hormone is listed in Table 16.

Several studies from Europe show very positive effects especially in corticoid-induced osteoporosis [1, 2] and in post-organ transplantation osteoporosis. In the latter the immunological effects of alfacalcidol may play an additional role and deserve further investigation.

The high risk of hip fracture in senile osteoporosis can be reduced by alfacalcidol. There is increasing evidence that the positive effects of the D-hormone on muscle metabolism may reduce the risk of falling and thereby contribute to the reduction in hip fracture events.

Most of the positive therapeuticc experience with alfacalcidol in post-menopausal osteoporosis has been established in Japan.

Table 16       Rationale for using alfacalcidol in different forms of osteoporosis

1. Increase of intestinal calcium absorption after activation in the liver 2. Decrease of PTH secretion by the parathyroid glands (= down-regulation of secondary hyperparathyroidism 3. Antiresorptive effect on bone tissue by reducing activity of osteoclasts 4. Stimulatory effect on osteoblasts (osteoblasts have D-hormone receptors; alfacalcidol is activated in part locally in bone tissue) 5. Improvement of mineralization of bone matrix and newly formed bone tissue 6. Positive effects on muscle metabolism and neuromuscular coordination (muscle cells have D-hormone receptors 7. Immunosuppressive, immunomodulatory, and antiproliferative effects

REFERENCES
1. Ringe JD, Cöster A, Meng T, Schacht E, Umbach R.
Treatment of glucocorticoid-induced osteoporosis with alfacalcidol/calcium versus vitamin D/calcium.
Calcif Tissue Int 1999; 63: 337-340

2. Reginster JY, Kuntz D, Verdickt W, Wouters M, Guillevi L, Menkes CJ, Nielsen K.
Prophylactic use of alfacalcidol in corticosteroid-induced osteoporosis.
Osteoporos Int 1999; 9: 75-81

The D-analogue alfacalcidol (1α-hydroxycholecalciferol) is a prodrug of calcitriol (= 1,25-dihydroxycholecalciferol). After intestinal absorption alfacalcidol is readily hydroxylated in the liver to 1,25-dihydroxycholecalciferol, i.e. the active D-hormone (see to question "Prevention and treatment of secondary hyper-parathyroidism in chronic renal insufficiency?, Fig. 8: special situation of alfacalcidol bypassing the kidney activation step). Interestingly there are data showing that the activation takes place to some extent also in bone tissue. This in vivo activation of alfacalcidol in liver and bone has some advantages:
- The increased intestinal calcium absorption is somewhat retarded, i.e. there is a lower risk of transient hypercalcemia and/or hypercalciuria as compared wiht primary administration of calcitriol.
- The amount of alfacalcidol that is activated in the bone tissue may increase the local osteoblastic activity.

These findings provide an important therapeutic advantage because the pro-drug technique offers greater pharmacological benefit and a wider therapeutic range due to continuous transformation to the active metabolite and contant distribution in a physiological dose to all target organs, and particularly for bone and parathyroid glands.

Table 17    Diffeences between calcitriol and alfacalcidol

Calcitriol	Alfacalcidol
- After oral intake absorption or immediate binding to small intestinal receptors - Plasma peaks of calcitriol and increased risk of hypercalcemia and hypercalciuria	- After oral intake absorption and activation mainly in the liver (25-hydroxylation) - Balanced plasma curve of calcitriol; lower risk of hypercalciuria and hypercalcemia - Advantage of additional activation in bone tissue

Taking together all prospective controlled studies performed with alfacalcidol in postmenopausal and corticoid-induced osteoporosis shows a clear reduction of vertebral fractures. In a separate study on hip fractures there was a significant effect of the D-analogue compared to placebo in reducing this type of fracture.

In contrast to other antiosteoporotic drugs, which have either antiresorptive or anabolic effects, alfacalcidol obviously acts by different additive mechanisms. The main effects at the level of the gut and parathyroid glands, and of bone and muscle resulting finally in a reduced fracture rate are shown in Figure 7.

Before starting a long-term treatment with alfacalcidol serum and urinary calcium should be controlled and the patient should be interviewed concerning his/her average dialy consumption of calcium-rich nutrients (milk, milk products, calcium supplements, plain vitamin D).

Significant hypercalcemia or hypercalciuria and recent kidney stones are, of course, contraindications for alfacalcidol.

If the daily calcium intake is above 1000mg; no additional calcium should be given. At average intakes between 400-600mg/day a supplement of 500 mg is recommended. In general, the daily supplement of calcium together with alfacalcidol should not exceed 500 mg.

Controls of uringary calcium should be performed at regular intervals during long-term alfacalcidol treatment.

Altogether, alfacalcidol is a safe drug and the risk of increases in serum or urinary calcium is very small when following the above recommendations.

Since alfacalcidol has antiresorptive and anabolic effects, all other anabolic and antiresorptive drugs are potential candidates for combined trials to evaluate whether additive effects can be achieved. Most of the possible combinations have not been studied by prospective controlled trials.

For the combination alfacalcidol/fluoride positive effects on the quality of newly formed bone substance were reported in the literature, but confirming data are still lacking.

The so far largest study has been performed by C. Gallagher with active vitamin D plus HRT. The effect on BMD was significantly higher than with HRT alone.

In a pilot study from our group 12 men with established idiopathic osteoporosis were treated with the combination alendronate/alfacalcidol/calcium at the respective doses of 10mg/1μg/500mg. The increase in BMD at the lumbar spine and femoral neck after 12 months was significantly higher than with alendronate/calcium or alfacalcidol/calcium givne separately.

Based on our clinical experience, we recommend combined treatment regimens, especially in very advanced cases of osteoporosis or in "treatment-resistant" patients. Alfacalcidol is a very interesting partner for all kinds of combinations due to its different effects on calcium metabolism, bone and muscle (see question "What is the rationale for using alfacalcidol in corticosteroid-induced, senile, post-transplantation, and postmenopausal osteoporosis?", Table 16).

The major pathogenetic factors inducing renal bone disease in patients wiht chronic renal insufficiency before or during hemodialysis are low serum calcium and increased phosphorus leading to secondary hyperparathyroidism.

The aim of prevention or treatment is to normalize both parameters. This can be achieved by alfacalcidol increasing serum calcium. The increasing trends in calcium level and the direct effects of alfacalcidol on the parathyroid glands will reduce PTH secretion. The addition of calcium carbonate will further slightly increase serum calcium and decrease serum phosphorus.

In complex forms of renal osteodystrophy with histological features of hyperparathyroidism and osteomalacia, alfacalcidol not only normalizes the former but also will improve the mineralization of the osteomalacic bone.

Plain vitamin D and 25-hydroxycholecalciferol are not indicated for prevention or therapy of renal bone disease. Both substances will not be sufficiently activated in patients with renal failure or nephrectomy.

Figure 8 shows the metabolism of vitamin D in general and the special situation of alfacalcidol bypassing the activation step in the kidney.

Vitamin D and analogues.

Therapeutic class (ATC): A11CC03.

REFERENCES
IMS

The active metabolite of vitamin D is 1,25(OH)2D3 (calcitriol). So, as One-Alpha® is only hydroxylated in the 1-position, it requires activation through 25-hydroxylation, which takes place in the liver.

In general, the use of One-Alpha® is efficient in patients with reduced liver function, e.g. in alcoholic liver disease and PBC.

In cases of severe hepatic dysfunction, the effect of One-Alpha® may be decreased, partly due to a decreased hydroxylation in the 25-position, but also due to factors common to any vitamin D metabolite (e.g. decreased enterohepatic circulation).

REFERENCES
The effect of oral 1 alpha hydroxy vitamin D3 and 1,25-(OH)2 D3 on the intestinal absorption of calcium and phosphate in primary biliary cirrhosis
Varghese Z, Epstein O, Farrington K, Newman S P, Moorhead J F, Sherlock S In: Vitamin D: basic research and its clinical application: proceedings of the 4th Workshop on Vitamin D, Berlin, 1979
Editor(s): Norman A W, Schaefer K, Herrath D von, Grigoleit H G, Coburn J W, DeLuca H F, Mawer E B, Suda T
Berlin: Walter de Gruyter, 1979: 1045-1049

Treatment of osteomalacia associated with primary biliary cirrhosis with oral 1-alpha-hydroxy vitamin D3
Compston J E, Crowe J P, Horton L W L
Br Med J 1979; 2: 309

Vitamin D metabolism and chronic liver disease.
Wills MR, Savory J.
Ann Clin Lab Sci 1984;14(3):189-97

Abnormal Vitamin D metabolism in patients with cirrhosis.
Hepner GW, Roginsky M, Moo JF.
Dig Dis 1976;21(7):527-32.

Previously the concentration of plain vitamin D was tested in an animal model. The strength of the concentration was measured in international units (IU). Today, the strength is measured in mcg.

As One-Alpha® is a chemical entity the strength is measured in mcg. There is no conversion factor from mcg to IU, but the potency of One-Alpha® may be from 2-5 times (or even more) the potency of plain vitamin D.

If patients are switched from plain vitamin D to One-Alpha® it will be safer and more advisable to carry out serum calcium evaluation and to start with a lower dose of One-Alpha® following our usual dosage recommendations.

BACKGROUND
1 mcg plain vitamin D equals 40 international units (IU).

REFERENCES
Biological activity of 1alpha-hydroxyvitamin D3 in the rat
Holick M F, Kasten-Schraufrogel P, Tavela T, DeLuca H F
Arch Biochem 1975; 166(1): 63-66

Nutritional agents and vitamins.
In: Martindale. The Extra Pharmacopoeia. Thirtieth Edition. Reynolds JEF, ed., The Pharmaceutical Press, 1993, p. 1059.

In its guidelines for defined daily dosis (DDD) the WHO states that DDD for alfacalcidol and calcitriol is 1 mcg for both drugs, saying that the bioequivalence is 1:1.

BACKGROUND
The comparison of One-Alpha® to 1,25(OH)2D3 is indirect by measuring the rise in serum 1,25(OH)2D3 concentration after One-Alpha® intake, showing a smaller peak compared to 1,25(OH)2D3, when given as a single dose.

This may be due to a fast distribution of One-Alpha® into fat, making less One-Alpha® available for immediate 25-hydroxylation in the liver.

Kimura et al. compared P-1,25(OH)2D3 during continuous administration of alfacalcidol and calcitriol. The authors felt that the oral administration of 1(OH)D3 may be more effective than 1,25(OH)2D3 in maintaining consistent plasma levels of 1,25(OH)2D3.
The authors did not discuss the achieved P-1,25(OH)2D3 which was almost 2-fold higher with alfacalcidol using two times higher doses of alfacalcidol, indicating a bioavailability ratio to the active 1,25(OH)2D3 of approximately 1:1.

Some authors have suggested that the bioavailability of 1,25(OH)2D3 may be lower after administration of One-Alpha® as compared to equal doses of 1,25(OH)2D3. However, One-Alpha® may possess biological effects not seen with 1,25(OH)2D3. Thus, Brandi et al. have suggested the existence of a suppressive effect of One-Alpha® on the parathyroid glands (i.e. on the P-PTH levels) which is independent of the P-1,25(OH)2D3 levels, that are achieved after oral or i.v. administration of One-Alph®. This effect is beneficiary in the prophylaxis and treatment of secondary hyperparathyroidism seen in chronic uraemia.

REFERENCES
Anatomical Therapeutic Chemical (ATC) Index with DDD's 1997.
WHO Collaborating Centre for Drug Statistics Methodology

Pharmacokinetics of Active Vitamins D3, 1 alpha-Hydroxyvitamin D3 and 1 alpha, 25-Dihydroxyvitamin D3 in Patients on Chronic Hemodialysis
Kimura Y, Nakayama M, Kuriyama S, Watanabe S, Kawaguchi Y, Sakai O
Clin Nephrol 1991; 35(2): 72-77

Pharmacokinetics of 1,25(OH)2D3 and 1(OH)D3 in normal and uraemic men.
Brandi L, Egfjord M, Olgaard K.
Nephrol Dial Transplant (2002);17:829-42

The DDD for One-Alpha® as well as calcitriol is 1mcg.

BACKGROUND
In its guidelines for defined daily dosis (DDD) the WHO states that DDD for alfacalcidol and calcitriol (administration route oral or parenteral) is 1 mcg for both drugs, saying that the bioequivalence is 1:1.

REFERENCES
Anatomical Therapeutic Chemical (ATC) Index with DDD's 1997.
WHO Collaborating Centre for Drug Statistics Methodology.

It is not recommended to add One-Alpha® injection to an infusion fluid.
One-Alpha® injection should always be given in a shunt as close as possible to patients, as it is done in haemodialysis patients, similarly it is not recommended to add One-Alpha® to parenteral nutrition.

BACKGROUND
Because of the possibility of absorption by the infusion container or tubing, it is not recommended to use One-Alpha® injection in CAPD patients (P Joffe). Instead it is recommended to use oral treatment, pulse or daily.

REFERENCES
1alpha-Hydroxycholecalciferol Adsorption to Peritoneal Dialysis Bags: Influence of Time, Glucose Concentration, Temperature, and Albumin
Joffe P, Ladefoged S D, Cintin C, Lehmann H
Nephrol Dial Transplant 1992; 7(12): 1249-1251

It is possible to dilute the One-Alpha® injection in a mixture of propylenglycol and isotonic NaCI 1:1.

It is very important that the diluted One-Alpha® injection is injected very slowly.

BACKGROUND
When children are treated with One-Alpha® injection the volume to be given is often so small that it will not be possible to give an exact dose.

This problem can be solved by diluting the injection with propylene glycol and isotonic NaCI.

Several studies have shown that alfacalcidol reduces the bone pain in osteoporotic patients.

Lindholm et al. found that pain was relieved in eight out of ten patients suffering from osteoporosis, who received a combined treatment of alfacalcidol and calcium. In addition, the increased well-being of patients led to an increase in physical activity.

Ringe et al. compared the efficacy of alfacalcidol with plain vitamin D in patients with established glucocorticoid-induced osteoporosis with or without vertebral fractures (treatment period 3 years). A significant decrease of back pain only in the group treated with alfacalcidol was found.

Crisp et al. found a significant reduction in the pain score in 10 women with osteoporotic vertebral crush fractures, who received a combination treatment of alfacalcidol, calcium supplementation, and female hormones.

REFERENCES
Combined treatment of post-menopausal osteoporosis: effect on muscle function and a new radiological method for assessing trabecular bone
Crisp A J, Buckland-Wright J C, Kauffmann E A, Gibson T
Curr Med Res Opin 1984; 8(10): 701-707

Changes in bone histomorphometry and bone mineral during treatment of osteoporosis with 1alpha-hydroxyvitamin D3 and calcium
Lindholm TS, Nilsson OS, Elmstedt E, Eriksson SA, Lindholm TC, Kyhle BR
Acta Vitaminol Enzymol 1981; 3(3): 170-176

Treatment of glucocorticoid-induced osteoporosis with alfacalcidol/calcium versus vitamin D/calcium.
Ringe JD, Coster A, Meng T, Schacht E, Umbach R.
Calcif Tissue Int 1999;65(4):337-40.

It is well accepted that the main factor leading to the development of secondary hyperparathyroidism is hypocalcaemia.

The factors that contribute to hypocalcaemia and secondary hyperparathyroidism include phosphate retention, decreased synthesis of calcitriol, skeletal resistance to the calcaemic action of PTH, an increased “set point” for calcium-regulated PTH secretion, and impaired degradation of PTH secondary to reduced renal function.

REFERENCES
Bone diseases in chronic renal failure and after renal transplantation.
E. Slatopolsky, J Delmez, In: Disorders of bone and mineral metaolism. Raven Press 1992, 905-934
Editors: Coe FL and Favus MJ

Yes it is safe. One-Alpha® is safely administered with Calcium channel blockers and antihypertensive drugs.

One-Alpha® corrects intestinal absorption of Calcium. This process involves extracellular Calcium mechanisms, while in the case of Ca-channel blockers their mechanism of actions is done intracellularly.

Of course it is possible to administer One-Alpha® alone, without Calcium.

One-Alpha® stimulates Calcium absorption in the intestine provided that the patient diet is rich in Calcium (Calcium is found in milk and dairy products). But since this is not the case in most Osteoporotic patients it is recommended to supplement them with Calcium.

This is not only in the case of One-Alpha®, but with all other anti-osteoporosis agents.

Recent studies involving more than 5000 elderly patients resident in nursing homes demonstrated that a daily dose of One-Alpha^® 1 mcg plus 500 grams of calcium  ensured optimal functional mobility and reduced the frequency of falls in those patients.

Monthly monitoring of serum calcium levels (ionized) will indicate if adjustment of One-Alpha^® dose is needed.

1. What is Osteoporosis?

Osteoporosis, which literally means "porous bone", is a disease in which the density and quality of bone are reduced. As the bones become more porous and fragile, the risk of fracture is greatly increased. The loss of bone occurs "silently" and progressively. Often there are no symptoms until the first fracture occurs.

Left: normal bone, right: osteoporotic bone

The most common fractures associated with osteoporosis occur at the hip, spine and wrist. The incidence of these fractures, particularly at the hip and spine, increases with age in both women and men.

Of notable concern are vertebral (spinal) and hip fractures. Vertebral fractures can result in serious consequences, including loss of height, intense back pain and deformity. A hip fracture often requires surgery and may result in loss of independent living.

The good news is that osteoporosis is now a largely treatable condition and, with a combination of lifestyle changes and appropriate medical treatment, many fractures can be avoided.

2. How osteoporosis occurs ?

The hormonal changes that take place at menopause are one reason why women are at greater risk of osteoporosis than men. Bone tissue loss generally begins after the age of about 40 years, when we are no longer able to replace bone tissue as quickly as we lose it. In women, however, the rate of bone tissue loss increases after menopause, when estrogen production stops and bones no longer benefit from its protective effect.

There are a number of other risk factors associated with osteoporosis:

• A close family member diagnosed with osteoporosis
• A family history of fractures resulting from minor bumps and falls
• Frequent falls
• A previous fracture
• Long-term enforced bed rest
• Little physical activity
• Low body weight
• Loss in height
• Periods stop for more than 12 months
• A diet low in calcium and vitamin D
• High alcohol intake
• Smoking
• Certain medications in long-term use such as corticosteroids
• Age 60+
• Chronic disorders such as anorexia nervosa, malabsorption syndromes including coeliac disease and Crohn's disease, chronic liver disease, primary hyperparathyroidism, post-transplantation, chronic renal failure, hyperthyroidism, Cushing's syndrome, arthritis

3. How common is osteoporosis?

Osteoporosis is one of the most common and debilitating chronic diseases, and a global healthcare problem. Around the world, one in three women and one in five men over the age of 50 will suffer an osteoporotic fracture. Although more common in older people, osteoporosis can also affect younger people.

Added to the above differences between both compounds, there is now a convergent body of evidence to suggest that alfacalcidol is reasonable, safe and effective option for all forms of osteoporosis.

Bone densitometry should be performed to prove whether the back pain is related to osteopenia or osteoporosis. An x-ray of the spine could show degenerative changes or fractures.

We would recommend  a normal diet (not poor calcium diet!) and 500mg calcium supplement per day. This will reduce the risk for new calcium-oxalate stones.

If there is osteoporosis we would treat this patient with a bisphosphonate (e.g. Fosamax 70 mg per week) and we would control renal calcium excretion. If urinary calcium is in the normal range we would add 0.25 mcg of alfacalcidol daily.