Calcinase (calcitonin) – Monograph

Table of Content

Calcinase (calcitonin) - Monograph

Introduction

Osteoporosis is the most common bone disease in humans and is characterized by low bone mass, microarchitectural deterioration, compromised bone strength, and an increased risk of fracture. In osteoporosis the absolute bone mass is so sufficiently reduced that fracture risk is increased even in the absence of significant trauma.

Osteoporosis is especially prevalent in older postmenopausal women. However, today experts have come to the realization that osteoporosis can affect everybody, independent of sex and age.

Enormous work and research on bone disorders done over past 10-20 years has contributed greatly to our understanding of osteoporosis, its causes, prevention and treatment. Osteoporosis is now identified as one of the most important diseases affecting the human race. While every eighth woman suffers from breast cancer, every third woman sustains a fracture due to osteoporosis.

The management of osteoporosis must target all aspects of the condition: bone mass should be maximized, bone microarchitecture (bone quality) must be maintained, fractures should be prevented and people who have already sustained a fracture should be rehabilitated to minimize associated pain and limitation of activities. Calcinase is a nasal spray of salmon calcitonin, which can achieve most of the goals of management of osteoporosis.

Osteoporosis: An Overview

Osteoporosis is a growing healthcare problem globally. Prevalence of osteoporosis increases with age and after menopause. As the older population in world rises, an increasing number of population will be affected by painful fractures and their deleterious consequences.

According to International Osteoporosis Foundation, one in three women and one in eight men above 50 years of age have osteoporosis.

Figure 1: Annual osteoporotic fractures in women compared with other diseases

In India, osteoporosis affects approximately 1 in 2 women, 1 in 4 men and almost 50 million Indians are at risk1.

Osteoporotic fractures are found to be more disabling than any other disease in women as suggested by the figure alongside.

Definition

According to NIH (National Institute of Health) Consensus Development Panel 2, "Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture."

Bone strength primarily reflects the integration of bone density and bone quality.

  • Bone density is expressed as grams of mineral per area or volume, and in any given individual is determined by peak bone mass and amount of bone loss.
  • Bone quality refers to architecture, tur nover, damage accumulation (e.g. microfractures), and mineralization.

In 1994, the World Health Organization (WHO) established bone mineral density (BMD) measurement criteria, allowing the diagnosis of osteoporosis before incident fractures3.

Table 1: Diagnostic categories for osteoporosis in postmenopausal women based on World Health Organization Criteria

Category Definition by bone density
Normal A value for BMD that is not more than 1 SD below the young adult mean value
Osteopenia A value for BMD that lies between 1 and 2.5 SD below the young adult mean value
Osteoporosis A value for BMD that is more than 2.5 SD below the young adult mean value
Severe osteoporosis A value for BMD more than 2.5 SD or below the young adult mean in the presence of one or more fragility fractures

Classification of Osteoporosis2

Osteoporosis is primarily classified as:
1. Primary osteoporosis
2. Secondary osteoporosis

Primary Osteoporosis

Primary osteoporosis is the more common of the two; 80% to 90% of all cases of osteoporosis are primary. Primary osteoporosis occurs mostly in older people and much more frequently in females. Primary osteoporosis can be subdivided into :

  • Postmenopausal (type 1) osteoporosis
  • Senile(or type II)
  • Idiopathic

A) Postmenopausal (Type I) Osteoporosis

This is the most common form of osteoporosis and it occurs in women between 51-70 years of age as a consequence of cessation of ovarian function. The loss of bone actually starts years beforehand and increases at the time of menopause. Cessation of oestrogen secretion leads to a decrease in IL-6 and other cytokines, which in turn leads to increased recruitment and activation of osteoclasts. In addition, bone becomes more sensitive to the resorption stimulating action of parathyroid hormone. As a consequence there is increased resorption of cancellous bone in the vertebra and hip bones, with a corresponding increase in risk of fractures. This postmenopausal form of osteoporosis obviously occurs in women only, but men are also subject to increased bone resorption as a consequence of testosterone deficiency, though at a later stage in life.

B) Involutional (age-related, Type II, senile) Osteoporosis

Postmenopausal osteoporosis merges imperceptibly into the age-related type, which represents part of the aging process and includes increased osteoclastic activity. Study of bone biopsies taken from normal individuals of different age groups show that bone is not an atrophic tissue in the older age groups. It presents the picture of osseous remodeling. Causative factors for involutional osteoporosis are: decreased mobility, defective vitamin D metabolism, insufficient calcium, and mild secondary hyperparathyroidism. This type of osteoporosis develops after 70 years of age and is now only twice as frequent in women as in men. Cortical bone, especially that of the femoral neck, radius and pelvic bones are involved. The arbitrary separation of osteoporosis into Type I and II - at this stage in patients' lives (>70 years) is of little practical value.

C) Idiopathic

This occurs in children and young adults and the cause is not known.

Secondary Osteoporosis

Secondary osteoporosis occurs as a well-defined feature of another disease, condition or medical therapy. Secondary osteoporosis can occur in both sexes and in children as well as adults.

Table 2: Secondar forms of osteoporosis

Endocrine or metabolic Medication

Acromegaly

Anorexia nervosa

Athletic amenorrhea

Diabetes mellitus-type 1

Hemochromatosis

Hyperadrenocorticism

Hyperparathyroidism

Hyperprolactinemia

Thyrotoxicosis

Glucocorticoids

Gyclosporine

Excess thyroid

hormone

GnRH agonists

Methotrexate

Phenobarbital

Phenothiazines

Phenytoin

Heparin, prolonged treatment

Collagen/genetic disorders Nutritional

Ehlers-Danlos syndrome

Glycogen storage diseases

Homocystinura

Hypophosphatasia

Marfan syndrome

Osteogenesis imperfecta

 

Alcoholism

Calcium deficiency

Chronic liver disease

Malabsorption syndrome

Vitamin D deficiency

GnRH = gonadotropin-releasing hormone

Pathogenesis

Bone is a specialized form of connective tissue composed of an organic matrix mineralized by the deposition of calcium phosphate. This gives rigidity and strength to the skeleton together with some elasticity.

The overall architecture of bone is divided into cancellous bone (also referred to as trabecular bone) and cortical bone. Cortical bone forms a compact shell around the more delicate cancellous bone, which is formed by an interconnective latticework of trabeculae. In general, the peripheral skeleton is composed primarily of cortical bone, while the axial skeleton is composed of both cancellous and cortical bone. Because the surface area of cancellous bone far exceeds that of cortical bone, and is more metabolically active, cancellous bone is more severely affected if bone remodeling becomes uncoupled. During the accelerated period of bone loss immediately after menopause, cancellous bone loss increases 3-fold, while rates of cortical bone loss are slower4,5.

Figure 2: Types of bones

After linear growth ceases, bone is in a constant state of remodeling, with repeated cycles of bone resorption followed by deposition of new bone. In patients without osteoporosis, bone resorption followed by bone formation is sequential without overall loss of bone. This constant bone turnover is critical to overall bone health, as it repairs microfractures and remodels the bony architecture in response to stress. Additionally, bone is a major reservoir for calcium, and in various physiologic and pathologic situations, bone mass may be sacrificed to satisfy intra- and extracellular calcium needs.

Osteoporosis is essentially caused by aberrations in bone remodeling leading to bone fragility. During the childhood and young adult years, bone formation exceeds bone destruction; therefore there is a steady increase in bone mass. However, between the ages of 25 and 35 years, humans reach an apex, which signifies their peak bone mineral density (BMD). This peak density is influenced by a number of factors including genetics, nutrition, exercise and hormones. After this point, the balance changes to favour osteoclastic activity4. Subsequently, both men and women lose BMD at a rate of approximately 3-4% per decade. This process continues throughout a man's life. However, among women, bone loss accelerates to approximately 9% per decade for 10-20 years following menopause due to the decreased estrogen concentrations in the body and then stabilises at a rate of 3-4% per decade. Estrogen receptors are located throughout the body including sites in bone tissue, intestine, and kidney. Before menopause, estrogen interacts with these receptors and favourably affects bone remodeling and calcium balance. After menopause, serum estrogen levels drop; resulting in decreased estrogen receptor stimulation, increased production of cytokines, and increased osteoclastic activity. The remodeling balance is disrupted, and bone breakdown exceeds bone production, rendering the bone matrix unstable and increasing the risk of fracture. Prevention and treatment of osteoporosis involves manipulation of the remodeling cycle and number of remodeling sites.

Bone Remodeling6

At the cellular level, bone remodeling can be conceptualized as consisting of approximately 1 million bone remodeling units. These remodeling units are approximately 1-2 mm long and 0.2-0.4 mm wide, and are comprised of a population of osteoclastic cells in front and a group of osteoblastic cells in the rear. The remodeling units are also composed of a central vascular capillary, a nerve supply and associated connective tissue.

Bone remodeling units combine the sequential action of osteoclasts, which resorb bone leaving a lacuna or cavity, and the subsequent action of osteoblasts which synthesize new bone. The lifespan of an individual bone remodeling unit is 6 to 9 months.

Figure 3: Bone remodeling unit

Resorption

In a coupled process, bone is resorbed through the action of osteoclasts which are large multinucleated cells derived from monocyte/macrophage lineage. The most characteristic feature of monocytes is the ruffled border of finger-shaped projections of cell membrane that mediate the resorption of calcified bone matrix. The mineral content of the matrix is first dissolved in the acidic environment of the ruffled border and the remaining protein components of the matrix (primarily collagen) are then degraded by proteolytic enzymes secreted into the resorption space. The result is the dissolution of the bony matrix of the trabeculae to form a cavity or lacuna.

Figure 4: Resorption through osteoclast

Bone Formation

As the remodeling unit advances, osteoclasts leave the resorption site and osteoblasts derived from multipotent mesenchymal stem cells move in to cover the excavated area and begin the process of new bone formation by secreting osteoid which is eventually mineralized into new bone.

They first lay down a new protein matrix, principally composed of type I collagen. Type I collagen is initially secreted in the form of a precursor, which contains peptide extensions at both the amino-terminal and carboxyl ends of the molecule.

Individual collagen molecules become interconnected by the formation of pyridinoline cross-links which provide extra strength and are unique to bone. Osteoblasts also secrete other proteins that are incorporated into the bone matrix, including osteocalcin and osteonectin.

Two stages of mineralization then follow which are mediated by osteoblasts. Osteoblasts are essential to the process of mineralization which involves the deposition of hydroxyapatite. Osteoblasts are thought to regulate the local concentrations of calcium and phosphate in such a way to promote the formation of hydroxyapatite. First, hydroxyapatite crystals are deposited between the collagen fibrils. Alkaline phosphatase located on the membrane of osteoblasts is thought to play a role in this mineralization. The second stage occurs over the course of several months as additional mineral is added to the resorption cavity.

Figure 5: Bone formation by osteoblasts

Figure 6: Collagen fibres

Rate of Bone Turnover7,8,9,10

A high bone turnover rate can lead to weakening of bone strength and increased fracture risk by increasing the amount of bone undergoing the secondary slow phase of mineralization. A high bone turnover rate may weaken bone structure by disrupting the trabeculae and, as a consequence, high bone turnover rates may be an independent risk factor for vertebral and hip fracture. Bone turnover releases a number of biochemical byproducts or markers as a consequence of the physiological action of osteoblasts and osteoclasts. These turnover markers can be found in the serum and urine and are categorized as markers of bone formation or bone resorption.

Figure 7: Mineralization of bone

Bone Microarchitecture and Bone Strength 11

Bone mass measured by BMD explains about 60% to 85% of the variation in bone strength, and models of fracture risk have focused predominantly on losses of bone mass. However, the underlying microarchitecture of bone, in addition to bone mass, also affects bone strength. Bone mechanical strength is related to the shape, width and connectivity of the cancellous bone. Bone loss that causes discontinuity within the trabeculae irreversibly weakens the structural integrity of the bone, a more serious consequence than mere thinning of the trabeculae. This is referred to as “loss of connectivity.” Once the trabeculae are disrupted, deposition of new bone matrix may merely thicken the remaining trabeculae, rather than restoring continuity, so the bone may never be able to return to normal strength.

Changes in bone microarchitecture with loss of bone mass have been directly visualized in bone biopsy samples using 3-D microcomputed tomography. Using this technique, significant changes over time were found in trabecular architecture of bone from postmenopausal women.

After one year, biopsies from these women showed decreased bone volume and trabecular number, and increased trabecular separation. Alterations in bone architecture were also associated with increased bone turnover measurements. These post- menopausal women also had a loss in BMD over the course of the study12.

Figure 8: Trabecular bone

Risk Factors for Osteoporosis13

Osteoporosis is a preventable and treatable disease, but because there are no warning signs until a fracture occurs many people are not diagnosed in time to receive effective therapy during the early phase of the disease. Certain factors are linked to the development of osteoporosis. Some of these are modifiable while others are not.

Non Modifiable Risk Factors

  • Gender: Chances of developing osteoporosis are greater in women. Women have less bone tissue and lose bone more rapidly than men because of the changes involved in menopause.

  • Age: Risk of osteoporosis increases with age.

  • Body size: Small, thin-boned women are at greater risk

  • Ethnicity: Caucasian and Asian women are at highest risk.

  • Family history: Susceptibility to fracture may be, in part, hereditary. People whose parents have a history of fractures also seem to have reduced bone mass and may be at risk for fractures.

  • Personal history of fracture

Modifiable Risk Factors

  • Cigarette smoking

  • Diet low in calcium/vitamin D

  • Use of glucocorticoids, anticonvulsants and certain other drugs

  • Excessive alcohol intake

  • Sedentary lifestyle

  • Estrogen deficiency at an early age (<45 yrs)

  • Environmental risks (loose rugs, dark stairs, etc.)

  • Poor eyesight

Clinical Presentation 14

Fractures are among the most dreaded manifestations of osteoporosis. The most important causes of fractures in osteoporosis are an increased tendency to fall, decreased resistance to minimal trauma and low bone mass. Osteoporosis, the silent thief, usually remains asymptomatic until the weakened bone fractures. The most common sites of osteoporotic fractures are the spine, femoral neck and distal radius.

Clinical Signs and Symptoms

  1. Early: Microfractures, little or no pain
  2. Spontaneous fracture (under simple stress):
    Coughing, rolling in bed, getting up, bending over
  3. Common sites:
    • Femoral neck
    • Forearm/distal radius: Colles fracture
    • Spine
  4. Associated pain
    • Dull aching pain or sharp, severe pain
  5. Decrease in height
  6. Dowager 's hump or kyphosis

The earliest symptom of osteoporosis is often an episode of acute back pain in the middle to low thoracic or high lumbar region, occurring during rest or routine activity. Pain intensifies with sitting or standing and is relieved by bed rest in the fully recumbent position. The acute fracture does not usually affect neurologic findings.

Vertebral fractures due to osteoporosis are often referred to as compression fractures and are categorized as either wedge fractures or crush fractures. In a wedge fracture, the anterior portion of the vertebra collapses. In a crush fracture, the entire vertebra collapses. Wedge fractures are very common in osteoporotic patients.

As the osteoporotic individual ages, continued compression fractures of thoracic vertebrae cause the spine to curve.Curvature of the spine characteristic of postmenopausal osteoporosis is called kyphosis or "dowager 's hump". Curvature of the spine can result in the loss of several inches of height.

Diagnosis of Osteoporosis

1. History and Physical Examination

The history and physical examination are neither sensitive enough nor sufficient for diagnosing primary osteoporosis. However, they are important in screening for secondary forms of osteoporosis and directing the evaluation.

2. Radiology15

Radiography reveals recognisable bone loss only when 25%-30% of bone density has been lost, at which time osteoporosis is generally considered to have developed.

Films of spine may show vertebral changes such as loss of horizontal trabeculations, biconcavity, anterior wedge fractures, and compression fractures.

At present, the main role of radiography is in the diagnosis of fractures secondary to osteoporosis.

3. Bone Mineral Density (BMD) Measurements

Indications For Bone Densitometry16

  1. Estrogen status:
    • Premature menopause (< 45 years)
    • Prolonged secondary amenorrhoea (> 1 year)
    • Primary hypogonadism
  2. Corticosteroid therapy - e.g. prednisolone 7.5 mg/day or more with an expected use of more than 6 months
  3. Maternal family history of hip fracture
  4. Low body mass index (< 19 kg/m2)
  5. Chronic disorders associated with osteoporosis
  6. Radiographic evidence of osteopenia and/or vertebral deformity
  7. Previous fragility fracture, particularly of the spine or wrist
  8. Loss of height, thoracic kyphosis

a. Single and Dual-Energy X-ray Absorptiometry (SXA, DXA)20,21,22

Single and Dual-energy X-ray Absorptiometry determine bone mass by measuring the decrease in the strength of radiation that passes through tissue at the site being evaluated. They assess the mineral content of the whole skeleton, as well as of specific sites, including those most vulnerable to fracture. The term bone mineral content describes the amount of mineral in the specific bone site scanned, from which a value for BMD can be derived by dividing the bone mineral content by the area or volume measured.

In single-energy absorptiometry, bone mineral is measured at appendicular sites, such as heel or wrist. It is more precise than single-photon absorptiometry (SPA).

Dual-energy absorptiometry measures bone mineral at sites such as the spine and hip; it can also measure total body bone mineral.

Of the many techniques developed to assess bone mass, bone mineral or other related aspects of skeletal mass or structure, the most highly developed technically and the most thoroughly validated biologically is DXA, which is regarded as the 'gold standard'.

b. Ultrasound 22,15

Quantitative ultrasound (QUS) is used to assess skeletal status in osteoporosis. The principle underlying this technique is that the speed at which ultrasound waves move through bone is determined by the density and inherent material quality of bone. The higher the bone density, the higher the speed of ultrasound.

The use of QUS techniques has been best established for calcaneal systems. Its low cost and portability make QUS more attractive for use in assessing the risk of fractures in larger populations than may be appropriate for bone densitometry by X-ray absorptiometry.

c. Computed Tomography15

Quantitative computed tomography (QCT) with a suitable software package enables the absorption by different calcified tissues to be determined so that areas such as the vertebral body may be studied. The technique measures true density with the results expressed in g/cm3.

OCT has been applied to both the appendicular skeleton and to the spine. Cancellous bone in the spine and radius is highly suitable for assessment by QCT. Trabecular diameter and intertrabecular spaces can be measured using high resolution CT and abnormal trabecular architecture identified.

d. Magnetic Resonance Imaging (MRI)17,18

Magnetic resonance imaging (MRI) permits visualization of musculoskeletal tissues without using ionizing radiation. Magnetic resonance (MR) imaging offers the ability to examine the density of the trabecular and cortical compartments as well as the pattern of trabecular microarchitecture including apparent bone volume fraction, apparent trabecular thickness, apparent trabecular number, and apparent trabecular separation.

4. Biochemical Markers of BoneTurnover 19

In general, bone turnover markers are either (1) enzymes or proteins secreted by osteoblasts or osteoclasts; or (2) biochemical products resulting from the formation or breakdown of type I collagen, the primary component of new bone matrix.

The primary use of biochemical markers is for monitoring the response to treatment. With the introduction of antiresorptive therapeutic agents, bone remodeling declines rapidly, with the fall in reabsorption occurring earlier than the fall in formation.

Inhibition of bone reabsorption is maximal within 3 to 6 months. Thus, measurement of bone resorption markers prior to initiating therapy and 4 to 6 months after starting therapy provides an earlier estimate of patient response than bone densitometry.

Management of Osteoporosis

The primary goal of management of osteoporosis is to prevent fractures. This can be accomplished by:

  • Achieving the highest possible peak bone mass
  • Preventing further bone loss, and
  • Minimising chances for injury.

These objectives can be addressed through lifestyle modifications and pharmacologic therapy.

Lifestyle Modifications

1. Adequate Intake of Calcium and Vitamin D 23

Deficiency of calcium and vitamin D contributes to alterations of bone remodeling and bone integrity. Calcium absorption decreases with aging. Vitamin D deficiency is involved in the pathogenesis of osteoporosis, particularly that of senile osteoporosis.

Calcium and vitamin D combination is the accepted baseline treatment for osteoporosis and also is used as a preventive measure, particularly for frail elderly patients. Plain vitamin D can be used to treat primary vitamin D deficiency. However, calcitriol (1,25 (OH) 2 D 3), which is the active form of vitamin D, or an active analog like alfacalcidol are required to treat 1,25 (OH)2D3 deficiency or 1,25 (OH)2D3 resistance. Calcitriol is also useful in postmenopausal osteoporosis as it acts directly on osteoclasts and/or through increased TGFβ production to promote apoptosis of osteoclasts.

Vitamin D therapy may have additional benefits for very elderly patients, because it increases muscle strength and thus may reduce the number of falls and possibly fractures. The optimal effective dose of vitamin D is 400 to 1000 IU/d. The recommended dose of calcium for elderly women and men is 1500 mg/d. Women on hormone replacement therapy (HRT) need 1000 mg/d.

2. Exercise 13

Peak bone mass is attained by age 35, and thereafter adults need to maintain it. In both children and adults, regular weight-bearing or bone-stressing exercise is essential for maintaining bone mass.

Physical activity may have a twofold contribution to reducing fracture risk.

  1. It may enhance bone strength by optimizing BMD and improving bone quality and
  2. It has the potential to reduce the risk of falling.

The emphasis of physical exercise programs in elderly patients with osteoporosis should be on improving muscle strength and balance. The exercise should be weight bearing and easy to complete and should fit into their daily routine. A program of walkng, sitting, and standing exercises, or water aerobics, can be recommended to start with and gradually increased to more rigorous activity. For patients who have already had an osteoporotic fracture, physical exercise program can help reduce pain and increase functional capacity. Patients with vertebral fractures benefit from resistance exercises that strengthen back extensor muscles.

3. Avoidance of Tobacco Use and Excessive Alcohol Intake

Patients should be advised to avoid tobacco smoking and reduce alcohol intake.

The use of tobacco products is detrimental to the skeleton as well as to overall health.

4. Prevention of Fall

In addition to exercises, strategies to reduce risk of falling include, but are not limited to, checking and correcting vision and hearing, evaluating any neurological problems, reviewing prescription medications for side effects that may affect balance and stability and providing a check list for improving safety at home.

Pharmacotherapy

Pharmacotherapy should be initiated in:

  • Postmenopausal women who experienced fragility or low-impact fracture
  • A person with BMD T-scores below -2.0 by hip DXA with no risk factors
  • A person with BMD T-scores below -1.5 by hip DXA with one or more risk factors

Pharmacologic Options For the Prevention and/or Treatment of Postmenopausal Osteoporosis are:

1. Bisphosphonates 24

Bisphosphonates are a class of drugs that reduce bone loss, increase bone density in both the spine and hip, and reduce the risk of spine and hip fractures by directly inhibiting resorption and hindering recruitment and activity of the osteoclasts at the surface of the bone. Alendronate and risedronate are examples of drugs in this category. They are approved for:

  • Prevention of postmenopausal osteoporosis
  • Treatment of postmenopausal osteoporosis
  • Prevention of glucocorticoid-induced osteoporosis
  • Treatment of glucocorticoid-induced osteoporosis
  • Treatment of osteoporosis in men
  • Treatment of Paget's disease

2. Estrogen/Hormone Therapy (ET/HT)24

Estrogen therapy has a consistent positive effect across trials in respect to increasing BMD both in younger premenopausal women and older postmenopausal women. Estrogen receptors have been demonstrated on osteoblasts and on other cells in the bone microenvironment but the precise mechanism of estrogen action is still unclear.

Estrogen/hormone therapy (ET/HT) is approved for the prevention of osteoporosis, relief of vasomotor symptoms and vulvovaginal atrophy associated with menopause. Because of the risks, ET/HT should be used in the lowest possible doses for the shortest duration to meet treatment goals.

3. Parathyroid hormone 24

Endogenous PTH is an 84-amino acid peptide that is largely responsible for calcium homeostasis. Exogenously administered PTH acts either directly on target cells or indirectly through the synthesis of 1,25-dihydroxyvitamin D3. Evidence suggests that parathyroid hormone has a dual action on bone, with both osteoblasts and osteoclasts being responsive to parathyroid hormone. Recombinant human parathyroid hormone given as a daily subcutaneous injection has been evaluated in osteoporosis. Treatment with parathyroid hormone produces incremental increases in bone mineral density, particularly of cancellous bone in the vertebrae, even after short periods of treatment. Parathyroid hormone is licensed in only a few countries at present.

4. Raloxifene 24

Selective estrogen receptor modulator, raloxifene has been approved for both prevention and treatment of osteoporosis in postmenopausal women. It functions as either antagonist or agonist at specific estrogen receptors. Raloxifene stimulates bone while blocking the effects of estrogen in the breast and uterus. Although it is a good choice of therapy for women with a history of breast or uterine cancer or for women with concerns about taking estrogen, it tends to induce vasomotor symptoms. Other side effects such as leg cramps and venous thrombohemolytic events have been reported. This class of drugs should be used with extreme caution for women who are perimenopausal because the drug is contraindicated in pregnancy.

5. Strontium Ranelate 24

Strontium ranelate has been shown to inhibit bone resorption without depressing bone formation in both in vitro and animal studies. Strontium is absorbed onto the bone surface and increases bone strength by being incorporated in a dose-dependent manner into bone tissue to change the crystal structure but without altering mineralization. The use of strontium, normally regarded as a trace element, may offer an alternative way of decreasing bone resorption.

6. Others 24, 25, 26

Calcitriol: This synthetic vitamin D analogue, which promotes calcium absorption, has been approved for managing hypocalcemia and metabolic bone disease in renal dialysis patients. However, no reliable data demonstrate a reduction of risk for osteoporotic fracture.

Sodium fluoride: Through a process that is still unclear, sodium fluoride stimulates the formation of new bone. The quality of bone mass thus developed is also uncertain, and the evidence that fluoride reduces fracture risk is conflicting and controversial.

Tibolone:Tibolone is a tissue-specific, estrogen-like agent that may prevent bone loss and reduce menopausal symptoms but it does not stimulate breast or uterine tissue.

Drawbacks of Currently Approved Therapies27

There are various options available for management of osteoporosis but they all are having some inherent drawbacks :

References

1. India Today 2003; 17 Nov.
2. NIH (National Institutes of Health) consensus development Panel on Osteoporosis Prevention, Diagnosis and Therapy. JAMA 2001; 285: 785-95.
3. Bone Mineral Res 1994; 9:1137-44.
4. Assessment of fracture risk and its application to screening for Postmenopausal osteoporosis. Report of a WHO study group. World Health Organ Tech Rep Ser. 1994; 843: 1-29.
5. Osteoporos Int 1998; 8 (Suppl 4): S1-S88.
6. Endocr Rev 2000; 21: 115-137.
7. Bone 1996; 18: 197S-201S.
8. J Bone Miner Res 1996; 11: 1531-1538.
9. J Clin Densitom 1999; 2: 323-342.
10. Osteoporos Int 2002; 13: 349-52.
11. Skeletal Tissue Mechanics. New York: Springer - Kerlag; 1998.
12. Calcif Tissue Int 2003; 73: 423-432.
13. Clin Geriat Med 2002; 18 (3): 529-555.
14. Clin Symposia 1995; 47 (1): 17-20.
15. Diagnosis In: Stevenson J C, Marsh MS eds. " An Atlas of Osteoporosis" 2nd edition. The Parthenon Publishing Group 2000; 24-26.
16. Osteoporosis Int 1997; 7: 390-406.
17. Bone 1998; 22 (Suppl 5): 149S-153S.
18. Osteoporosis Int 2005; 16(9): 1124-33.
19. Harrison's Principles of Internal Medicine 15th ed. McGraw Hill, USA 2001; 2: 2226-2237.
20. Med Clin N Am 2003; 87: 1039-1063.
21. Am J Obstet Gynecol 1987; 156: 1342-46.
22. Report of a WHO scientific group. Prevention and Management of Osteoporosis. WHO Technical Report series 2003; 921.
23. Calcif Tissue Int 1999; 65: 295-306.
24. Akesson K, New approaches to pharmacological treatment of osteoporosis. Bulletin of World Health Organization 2003; 81: 657-664.
25. J Bone Miner Res 1996; 11: 46-55.
26. N Engl J Med 1996; 322: 802-809.
27. Prim Car Clin Office Pract 2003; 30: 711-741.

Calcinase: Intranasal (Salmon) Calcitonin Spray

Introduction1

Calcitonin is a polypeptide hormone secreted by the parafollicular (C-cells) of thyroid glands and plays a role, along with parathyroid hormone and 1,25-(OH)2D3, in calcium homeostasis. Calcitonin, which is secreted in response to high calcium concentrations in the blood, inhibits bone resorption and increases renal calcium excretion.

Chemical Structure1

Although more than 15 different calcitonins have been identified, only four (human, salmon, porcine and an analog of eel calcitonin) are available for therapeutic use. All calcitonin structures consist of 32 amino acids in a single chain, with a ring of seven amino-acid residues at the N-terminus, the sequence of which differs from species to species. Salmon calcitonin differs from human calcitonin in 16 amino-acid residues.

Mechanism of Action

Salmon calcitonin is approximately 40 to 50 times more potent than human calcitonin and longer acting due to its greater affinity for receptor binding sites.

The mechanism of action of salmon calcitonin mimics the physiological action of human calcitonin.

1. Action on Osteoclasts 1,2

Inhibits bone resorption by binding to calcitonin receptors on osteoclasts.

  • Receptor functions through activation of adenylate cyclase and phosphatidyl/ calcium pathways.
  • Binding of Calcitonin to its receptors on osteoclasts results in a fast (in minutes) loss of the ruffled border, cessation of motility and pseudopodial and margin retraction and inhibition of osteoclast secretion of proteolytic enzymes.
  • The number of osteoclasts adhered to bone decreases in vivo within half an hour.
2. Action on Osteoblasts3
  • Increases cell proliferation and alkaline phosphatase activity of human osteoblast-line cells in vitro in a concentration-dependent manner.
  • Data also suggest that small numbers of calcitonin receptors may be found on various osteoblast-line cells.

3. Analgesic Action 1,4

Various mechanisms have been proposed for its analgesic action.

  • Increased β-endorphin release.
  • Effects on central serotonergic or monoaminergic pathways.
  • Effects on intracellular calcium levels in CNS.
  • Direct action on specific receptors in CNS.
  • Decreased synthesis of prostaglandins or other humoral factors.

Pharmacokinetics5

Pharmacokinetic parameters of intranasally administered calcitonin (salmon) are difficult to quantitate due to the inadequate sensitivity and uncertain specificity of the available immunoassay methods used in the studies.

Peak plasma concentrations of drug appear 31-39 minutes after nasal administration compared to 16-25 minutes following parenteral dosing.

In normal volunteers approximately 3% (range 0.3%-30.6%) of a nasally administered dose is bioavailable compared to the same dose administered by intramuscular injection.

The half-life of elimination of calcitonin-salmon is calculated to be 43 minutes.

There is no accumulation of the drug on repeated nasal administration at 10 hour intervals for up to 15 days. Absorption of nasally administered calcitonin has not been studied in postmenopausal women.

Doses higher than the recommended dose result in higher blood levels (as shown by an increase in AUC) but relative bioavailability does not increase. As is the case with other polypeptide hormones, there is very little value in monitoring plasma levels of calcitonin (salmon) since these are not directly predictive of the therapeutic response. Hence, calcitonin activity is to be evaluated by using clinical parameters of efficacy. Plasma protein binding is 30 to 40%.

Indications5

Calcinase is indicated for:

  • Treatment of postmenopausal osteoporosis
  • Bone pain associated with osteolysis and/or osteopenia.
  • Paget's disease of bone (osteitis deformans).
  • Neurodystrophic disorders (synonymous with algodystrophy or Sudeck's disease) due to various etiological and predisposing factors such as posttraumatic painful osteoporosis, reflex dystrophy, shoulder-arm syndrome, causalgia, drug-induced neurotrophic disorders.

Dosage and Administration5

Calcinase is for intranasal use only. Calcinase delivers 200 IU calcitonin (salmon) per actuation.

Osteoporosis: The recommended dosage of Calcinase for the treatment of established post-menopausal osteoporosis is 200 IU once a day administered intranasally, alternating nostrils daily. Use of calcitonin (salmon) nasal spray is recommended in conjunction with adequate calcium (at least 1000 mg elemental calcium) and vitamin D (400 IU per day) intake to prevent progressive loss of bone mass. Calcitonin (salmon) for the treatment of postmenopausal osteoporosis is to be administered on a long-term basis.

Bone Pain Associated with Osteolysis and/or Osteopenia: 200-400 IU daily. Up to 200 IU may be administered as a single dose; in cases where a higher dosage is required it should be given in divided doses. Dosage should be adjusted to the individual patient's needs.

Paget's Disease: 200 IU daily as a single dose. In some cases 400 IU in divided doses may be necessary at the beginning of therapy.

Treatment should be continued for at least 3 months, or longer if required. Dosage should be adjusted to the individual patient's needs.

Neurodystrophic Disorders: Early diagnosis is essential and treatment should start as soon as the diagnosis is confirmed. 200 IU daily in a single dose over a period of 2-4 weeks. An additional 200 IU may be further administered every second day for up to 6 weeks depending on clinical progress.

Use in Pregnant Women 5

There are no adequate and well controlled studies in pregnant women or nursing mothers. Animal studies have shown no embryotoxic and teratogenic potential. It appears that calcitonin (salmon) does not cross the placental barrier in animals. Calcitonin (salmon) nasal spray is not to be administered to such patients.

Use in Lactating Women 5

It is not known whether calcitonin (salmon) is excreted in human breast milk. In animals, calcitonin (salmon) has been shown to decrease lactation and to be excreted in milk. As a general rule, nursing should not be undertaken while a patient is on this drug since many drugs are excreted in human milk.

Use in Children 5

As intranasal calcitonin is indicated for postmenopausal women, its use in children is not appropriate.

Use in Elderly Patients/Renal Impairment/Hepatic Impairment

Extensive experience with the use of calcitonin (salmon) nasal spray in the elderly has shown no evidence of reduced tolerability or altered dosage requirements. The same applies to patients with altered renal or hepatic function.

Comparison of Intranasal and Penteral Administration of Salmon Calcitonin 6,7

Salmon calcitonin was previously marketed only in an injectable form, but now it is available as a nasal spray. Comparative studies evaluating the effects of intranasal and parenteral (intramuscular or subcutaneous) salmon calcitonin demonstrated equivalent biological effects when the intranasal dosage was approximately 2-4 times that of the parenteral dosage.

The biological efficacy of 100 IU of salmon calcitonin given intranasally was identical with or even slightly superior to that of 50 IU of salmon calcitonin administered intramuscularly. In a comparison between subcutaneous and intranasal administration of salmon calcitonin (primarily in patients with Paget's disease), more patients receiving parenteral therapy dropped out of the study because of adverse events (10% vs. 4%)7.

References

1. Drugs Aging 1996; 8(5): 378-400.
2. Endocr Regul 2003; 37(4): 225-38.
3. Calcif Tissue Int 1991; 48: 297-301.
4. Bone 2002; 30: 80S-88S.
5. PDR 2006.
6. Gennari C et al. Pharmacodynamic tests for evaluation of biological efficacy of synthetic salmon calcitonin nasal spray. In: Proc Int Symp Calcitonin '88. New Therapeutic Perspectives. The Nasal Spray. (Mazzouli GE, ed) 1988: 48-65
7. Calcif Tissue Int. 1993; 52 (2): 90-8.

Calcinase: Clinical Efficacy Data

Effect on Bone Mineral Density

1. Effect on Bone Mineral Density: Compilation of Various RCTs

The following table (Table 1) summarises data from randomized parallel group studies for changes in bone mineral density (BMD) or content (BMC) of lumbar vertebrae or distal forearm with intranasal salmon calcitonin (S) plus oral calcium (Ca) versus Ca only. All patients were postmenopausal women with established osteoporosis.

Table 1

2. A Double-blind Study of Intranasal Calcitonin for Established Oostmenopausal Oteoporosis
  • Aim
    To examine the effect of nasal calcitonin on bone and calcium metabolism in postmenopausal osteoporotic women.
  • Patients
    46 women with postmenopausal osteoporosis (55-75 years).
  • Intervention
    • Salmon calcitonin intranasally 200 IU/day or Placebo for 1 year
    • All patients received calcium 1 g/day
  • Evaluation
    • Clinical and laboratory follow-up every 3 and 6 months, respectively
    • Bone mineral density measured by DEXA at 4 sites (spine and cervical, Ward's triangle, and the trochanteric area of the hip).
    • Biochemical markers
  • Results
    • Calcitonin group showed a 6.8% increase in BMD after 6 months and 11% increase after 12 months (p ≤ 0.05).
    • In contrast, the placebo group showed 3.3% decrease in BMD after 6 months and a 5.0% decrease after 12 months.
    • No patient experienced side-effects and there were no complaints of local irritation
  • Conclusion
    • Nasal administration of 200 IU calcitonin daily, continuously for 1 year had a positive effect on the bone mass density in osteoporotic postmenopausal women

Kapetanos G et al. Acta Orthop Scand Suppl 1997;275:108-11

3. Treatment of Postmenopausal Osteoporosis with Salmon Calcitonin Nasal Spray: Evaluation by Bone Mineral Content and Biochemical Patterns
  • Aim
    To evaluate the efficacy of intranasal salmon calcitonin treatment in patients with postmenopausal osetoporosis as shown by clinical, biohumoral and densitometric variables.
  • Patients
    31 women with postmenopausal osteoporosis.
  • Intervention
    Salmon calcitonin nasal spray 100 IU/day plus calcium gluconate 1 g/day for 6months.
  • Evaluation
    • Bone pain was assessed using visual analogue scale
    • L2-L4 BMC (bone mineral content) was measured by dual photo scanner
    • Biochemical markers

  • Results
    • Bone pain score fell significantly (p<0.01) over 6 months
    • BMC rose significantly from 2.9 ± 0.21 to 3.15 ± 0.41 g/cm
    • Significant reduction of urinary hydroxyproline levels (from 37.2 to 28.2 mg/24 hrs)
    • No side-effects were registered.
  • Conclusion
    Salmon calcitonin is effective in preventing postmenopausal bone demineralization and in reducing associated pain. Furthermore, the improved compliance and ease of administration of salmon calcitonin nasal spray, as well as the significantly reduced side-effects, mean that calcitonin treatment may be continued for long periods of time.

Tolino et al. Int J Clin Pharmacol Ther Toxical 1993;31(7):358-60

Effect on Fracture Rate

1. Effect of calcitonin on vertebral and other fractures
  • Objective
    To evaluate the incidence of vertebral and non-vertebral fractures in published randomized clinical trials using calcitonin.
  • Methods
    • A minimum study duration of 6 months was accepted.
    • Randomized, comparative trials of calcitonin therapy and those that mentioned fracture as an outcome, were reviewed.
    • 14 trials with 1309 men and women were identified.
  • Results
    • 237 vertebral fractures in 1309 calcitonin-treated patients, and 271 vertebral fractures in 678 placebo-treated patients, giving an apparent efficacy of 55%.
    • In those studies that identified the frequency of non-vertebral fractures, calcitonin was associated with a significant decrease in risk.
    • Overall, fracture risk decreased by 57%

  • Conclusion
    Treatment with calcitonin is associated with a significant decrease in the number of vertebral and non-vertebral fractures.

Kanis J et al. Q J Med 1999;92:143-149

2. Effect of Intranasal Salmon Calcitonin on Bone Mass and Fracture Rates in Established Osteoporosis
  • Objective
    To study the dose related response of salmon calcitonin given intranasally on bone mass and bone turnover and the effect on fracture rates in elderly women with moderate osteoporosis
  • Design
    Double-blind, placebo controlled randomized study
  • Patients
    208 women aged 68-72 years with a bone mineral content of distal forearm on average 30% below the mean value for healthy premenopausal women.
  • Interventions
    The patients were allocated randomly in blocks of 4 to 2 years of treatment with either salmon calcitonin 50 IU, 100 IU, or 200 IU given intranasally or placebo. All patients received calcium supplement of 500 mg.
  • Main outcome measures
    Bone mineral content of distal forearm and lumbar spine as well as rates of vertebral and peripheral fractures after 2 years of treatment.

  • Results
    1. Bone mineral content
      The average changes in bone mineral content of the lumbar spine after two years of treatment were 1% in placebo group and 3% in salmon calcitonin 200 IU group. There was a significant dose related response to salmon calcitonin with an increase of 1%/100 IU both after one year and after two years of treatment.
    2. Fracture Rate
      There were fewer new patients with vertebral fractures and also peripheral fractures in all three groups receiving salmon calcitonin than in the placebo group.
    3. Adverse Events
    • There were no differences between rates of adverse events in the salmon calcitonin groups (25%-33%) and that in the placebo group (23%).
    • There were no clinically significant changes in safety parameters such as blood pressure and blood chemistry.
  • Conclusion
    Salmon calcitonin intranasally reduces the rate of new fractures and increases spinal bone mass in elderly women with moderate osteoporosis.

Overgaard K et al. BMJ 1992;305:556-61

3. PROOF (Prevent Recurrence Of Osteoporotic Fractures) Study
  • Objectives
    To determine the long-term efficacy and safety of salmon calcitonin nasal spray (NS) in the prevention of vertebral fractures in postmenopausal women with osteoporosis.
  • Design
    5-year, double-blind, randomized, placebo-controlled study
  • Patients
    1255 postmenopausal women with established osteoporosis.
  • Inclusion Criteria
    • White, Asian or Hispanic women
    • At least 1 year postmenopausal
    • 1-5 prevalent thoracic or lumbar vertebral compression fractures
    • Lumbar spine T-score < -2.0
    • No history of hip fracture
  • Treatment Protocol
  • Salmon calcitonin nasal spray of 100, 200 or 400 IU daily or placebo.
  • All subjects received 1000 mg/day calcium and 400 IU/day vitamin D.
  • Evaluation
    • Primary Endpoint
      • Patients with new vertebral fractures (relative risk to placebo).
    • Secondary Endpoints
      • Nonvertebral osteoporotic fractures (hip).
      • Biochemical markers of bone turnover.
      • BMD
  • Results
    Efficacy Profile
    At 5 years, 200 IU Salmon Calcitonin NS,

  1. Reduced the relative risk of developing new vertebral fractures by 33% (p=0.03).

  1. In women with 1-5 prevalent vertebral fractures at baseline, it reduced the relative risk of developing new vertebral fractures by 36%.

  1. Increased lumbar spine BMD significantly from baseline at each time point during the 5 years (p<0.01), whereas, there was no change in placebo group.

  1. Serum C-telopeptide (bone resorption marker) levels decreased significantly from baseline in the 200 IU and 400 IU salmon calcitonin nasal spray groups at all time points upto 5 years.
  • Safety Profile
    • Rhinitis was the only adverse event reported more frequently in the active treatment groups Vs placebo (22% vs 15%, p < 0.01) and it was mostly mild.
    • Headache was reported less frequently in the Salmon Calcitonin NS groups than in the placebo group (4% vs 7%, p = 0.03).
  • Conclusion
    • In postmenopausal women and the elderly, salmon calcitonin nasal spray:
      • Significantly reduces the risk of vertebral fractures.
      • Increases lumbar spine BMD.
      • Reduces the rate of bone turnover.
      • Is very well tolerated.

Chesnut CH et al. Prevent Recurrence of Osteoporotic Fractures (PROOF) Study.
Am J Med 2000; 109: 267-276.

Post-hoc Analysis of PROOF Study

A post-hoc stratification of the PROOF data was carried out to test the hypothesis that salmon calcitonin NS would be a particularly effective and safe therapy.

  • To prevent vertebral fractures in women above 70 years of age.
  • To reduce the risk of hip fracture in postmenopausal women.
  • Vertebral fracture reduction was calculated using odds ratio analysis.
  • Hip fracture reduction was calculated using Kaplan Meier statistical life table methods.
Results
  • In women ≥ 70 years salmon calcitonin reduces the relative risk of new vertebral fractures by 53%.
  • Salmon calcitonin reduces the risk of hip fractures by 68% (p=0.047) as compared to placebo.

Effect on Bone Quality (Bone Microarchitecture)

1. QUEST (Qualitative Effects of Salmon-Calcitonin Treatment) Study
  • Study Objectives
    • To evaluate the effect of salmon calcitonin nasal spray (Nasal Calcitonin) on trabecular microarchitecture
    • To evaluate the use of MRI in assessing trabecular structure in prospective clinical trials
  • Study Design
    • 2-year, double-blind, randomised, calcium-controlled study
  • Patients
    • 91 postmenopausal women
      • At least 5 years post-menopause
      • 15 vertebral fractures at baseline
  • Intervention
    • Salmon calcitonin 200 IU nasal spray or placebo
    • All patients received calcium 500 mg daily
  • Study Parameters
    • Bone Quality
      • Magnetic Resonance Imaging (MRI): Wrist, hip, calcaneus
      • Iliac crest bone biopsy: Histomorphometry
      • Micro CT of biopsy specimen
    • Bone Quantity
      • BMD (DEXA-Dual-Energy X-ray Absorptiometry): Spine, hip, wrist, heel.
    • Bone Turnover
      • Serum C-terminal telopeptide of type 1 collagen (CTx).
      • Serum/urine N-terminal telopeptide of type 1 collagen (NTx).
      • Serum Bone-specific alkaline phosphatase (BSAP).
  • Results
    1. Improvement and/or preservation of trabecular microarchitecture (as determined by high-resolution MRI measurements of apparent bone volume/ total volume, trabecular number, and trabecular spacing) at the distal radius in the postmenopausal osteoporotic women receiving salmon calcitonin nasal spray and calcium over 2 years compared with significant deterioration of trabecular microarchitecture in the women receiving only calcium.

  1. Women receiving salmon calcitonin nasal spray preserved trabecular microarchitecture at the distal radius and hip regardless of their change in BMD (gain or loss).
  2. T2* relaxation time (MRI)
    • T2* relaxation time is a composite measure of density and microarchitecture.
    • T2* relaxation time depends on:
      • Trabecular bone density (bone fraction).
      • Trabecular number, spacing and thickness (spatial distribution).
      • Trabecular orientation
    • A decrease in T2* equates to an increase in density and/or an improvement in microarchitecture features.
    • Preservation of bone quantity and structure, as measured by T2* relaxation time, was noted in the salmon calcitonin nasal spray group at the femoral neck and trochanteric regions of the proximal femur; significant deterioration of this T2* relaxation time was noted at multiple proximal femur sites in the calcium only control group.
      Thus, treatment with Nasal Calcitonin 200 IU nasal spray for 2 years resulted in:
      • Improvements (relative to placebo) in bone quality (i.e. BV/TV trabecular number and spacing) in the wrist, as, measured by MRI in vivo.
      • Improvements in bone quality (relative to placebo) expressed by T2* at the hip (femoral neck, upper and lower trochanters), statistically significant at the lower trochanter.

  • Nasal Calcitonin improves bone quality (as measured by MRI), regardless of the changes in BMD
  • Decrease in bone resorption of 24% (p<0.05), as evaluated by serum CTx.
  • No differences in the bone formation marker serum BSAP compared with, placebo
  • Histomorphometry confirmed the bone safety of Nasal Calcitonin; bone had a normal appearance with no signs of woven bone or mineralization defects
  • Conclusions
    • Nasal Calcitonin is effective, well-tolerated for osteoporosis, with proven, long-term safety and convenience for patients
    • The above findings, from one of the first studies in human subjects designed a priori to examine the effects of anti-resorptive treatment on trabecular microarchitecture, may provide a partial explanation of the mechanism of action of salmon calcitonin nasal spray.

Chestnut III CH et al. Results from the QUEST study, Journal of Bone and Mineral Research 2005; 20: 1548-1561.

Analgesic Effect

1. Analgesic Effect of Intranasal Salmon Calcitonin in the Treatment of Osteoporotic Vertebral Fractures
  • Objective
    To assess the analgesic effect of salmon calcitonin in the treatment of osteoporotic fractures of the spine.
  • Design
    Double-blind, randomized, placebo-controlled study.
  • Patients
    18 patients with 1 to 4 fractures of vertebrae were included.
  • Interventions
    Salmon calcitonin 200 IU daily or placebo for 4 weeks.
  • Evaluation
    Pain was graded according to a simple subjective scale and according to Huskinsson's visual analog scale.
  • Results
    A significant decrease in bone pain was observed after 7 days by 9 patients receiving salmon calcitonin. The level of pain in the nine patients receiving placebo, however, did not change.

  • Conclusion
    Intranasal salmon calcitonin can significantly reduce the pain of osteoporotic collapse of vertebra.

Pun Kk et al. Clin Ther 1989;11(2):205-209.

2. Pain Relief from Nasal Salmon Calcitonin in Osteoporotic Vertebral Crush Fractures
  • Aim
    To evaluate the efficacy of nasal salmon calcitonin in relieving post-fracture pain for early mobilization.
  • Design
    Double-blind, randomized, placebo-controlled study.
  • Patients
    32 men and 68 postmenopausal women with a non-traumatic vertebral fracture within previous 5 days.
  • Intervention
    • Salmon calcitonin nasal spray 200 IU or placebo for 28 days
    • Paracetamol was permitted as rescue medication
  • Evaluation
    Visual Analog Scale (VAS) during different locomotor function e.g. bed rest, sitting, standing and walking. Bone resorption was assessed using measures of total plasma calcium, albumin, alkaline phosphatase, creatinine, etc.
  • Results
    • Pain reduced dramatically in calcitonin group (p<0.001)
    • Lesser rescue medications taken by patients taking calcitonin
    • No. of patients who remained bedridden was significantly lesser in the calcitonin group
    • Hydroxyproline/creatinine ratio decreased in the calcitonin group (p<0.001), whereas it increased in the placebo group.
  • Conclusion
    • Nasal salmon calcitonin (200 IU daily) had an adequate analgesic effect and facilitated mobilization of patients with a recent osteoporotic vertebral fracture
    • Nasal salmon calcitonin and early mobilization also prevented massive bone loss during the period of bed rest.

Lyritis GP et al. Acta Orthop Scand 1997; 68(275): 112-114

Efficacy in Paget's Disease

Efficacy Safety and Tolerability of Salmon Calcitonin Intranasally in, Paget's Disease
  • Aim
    To investigate the efficacy, safety and tolerability of salmon calcitonin nasal spray in the long-term treatment of Paget's disease
  • Patients
    • 10 patients (58-74 yrs) with radiological lesions characteristic of Paget's disease
    • Serum alkaline phosphatase (sALP) levels at least 50% above normal range
    • Never treated for the disease before
  • Intervention
    200 IU of salmon calcitonin intranasally for 6 months
  • Results
    • sALP levels significantly dropped after 3 months of treatment (p<0.01).
    • Pain index decreased after 6 months (p<0.01).
    • Functional impairment index also decreased after 6 months (p<0.01)
    • Side-effects were not observed during the entire period of the study
  • Conclusion
    200 IU of salmon calcitonin given intranasally is effective, safe and well tolerated in the long-term therapy of Paget's disease.

Giustina A et al. Recenti Prog Med. 1989; 80(11): 599-602.

Calcinase Nasal Spray: Prescribing Information

Composition

Each spray delivers
Calcitonin (Salmon) BP .... 200 IU
Each ml contains:
Calcitonin (Salmon) BP .... 2200 IU
Benzalkonium Chloride NF
(as preservative) .... 0.01% w/v

Indications

Calcinase is indicated for:

  • Treatment of postmenopausal osteoporosis
  • Bone pain associated with osteolysis and/or osteopenia.
  • Paget's disease of bone (osteitis deformans).
  • Neurodystrophic disorders (synonymous with algodystrophy or Sudeck's disease) due to various etiological and predisposing factors such as posttraumatic painful osteoporosis, reflex dystrophy, shoulder-arm syndrome, causalgia, drug-induced neurotrophic disorders.

Dosage and Administration

Calcinase is for intranasal use only. Calcinase delivers 200 IU calcitonin (salmon) per actuation.

Osteoporosis: The recommended dosage of Calcinase for the treatment of established post- menopausal osteoporosis is 200 IU once a day administered intranasally, alternating nostrils daily. Use of calcitonin (salmon) nasal spray is recommended in conjunction with adequate calcium (at least 1000 mg elemental calcium) and vitamin D (400 IU per day) intake to prevent progressive loss of bone mass. Calcitonin (salmon) for the treatment of postmenopausal osteoporosis is to be administered on a long-term basis.

Bone Pain Associated with Osteolysis and/or Osteopenia: 200-400 IU daily. Up to 200 IU may be administered as a single dose; in cases where a higher dosage is required it should be given in divided doses. Dosage should be adjusted to the individual patient's needs.

It may take several days of treatment until the analgesic effect is fully developed. For continuing therapy the initial daily dosage can usually be reduced and/or the interval between administration prolonged.

Paget's Disease:200 IU daily as a single dose. In some cases 400 IU in divided doses may be necessary at the beginning of therapy.

Treatment should be continued for at least 3 months, or longer if required. Dosage should be adjusted to the individual patient's needs.

Note

In Paget's disease, treatment with calcitonin (salmon) should be given for periods ranging from at least several months to a few years. Treatment markedly reduces serum alkaline phosphatase and urinary hydroxyproline excretion, often to normal levels. However, in rare cases, alkaline phosphatase and hydroxyproline excretion levels may rise after an initial fall; the physician must then judge from the clinical picture whether treatment should be discontinued and when it may be resumed.

Disorders of bone metabolism may recur one or several months after treatment has been discontinued, necessitating a new course of Calcinase therapy.

Neurodystrophic Disorders: Early diagnosis is essential and treatment should start as soon as the diagnosis is confirmed. 200 IU daily in a single dose over a period of 2-4 weeks. An additional 200 IU may be further administered every second day for up to 6 weeks depending on clinical progress.

Pregnant Women
There are no adequate and well controlled studies in pregnant women or nursing mothers with calcitonin (salmon). Animal studies have shown no embryotoxic and teratogenic potential.

It appears that calcitonin (salmon) does not cross the placental barrier in animals. Calcitonin (salmon) nasal spray is not to be administered to such patients.

Lactating Women
It is not known whether calcitonin (salmon) is excreted in human breast milk. In animals, calcitonin (salmon) has been shown to decrease lactation and to be excreted in milk. As a general rule, nursing should not be undertaken while a patient is on this drug since many drugs are excreted in human milk.

Pediatric Use
As intranasal calcitonin is indicated for postmenopausal women, its use in children is not appropriate.

Use in Elderly Patients/Renal impairment/Hepatic Impairment
Extensive experience with the use of calcitonin (salmon) nasal spray in the elderly has shown no evidence of reduced tolerability or altered dosage requirements. The same applies to patients with altered renal or hepatic function.

Priming (activation) of pump: Before the first dose and administration, calcitonin (salmon) nasal spray should be at room temperature. To prime the pump, the bottle should be held upright and the two white side arms of the pump depressed toward the bottle until a full spray is produced. The pump is primed once the first full spray is emitted. To administer, the nozzle should be carefully placed into the nostril with the head in the upright position, and the pump firmly depressed toward the bottle. The pump should not be reprimed before each daily dose.

Contraindications

Hypersensitivity to synthetic calcitonin (salmon) or to any of the excipients of the formulation.

Warnings and Precautions

Periodic nasal examinations with visualization of the nasal mucosa, turbinates, septum, and mucosal blood vessel status are recommended. Nasal examinations should be performed before treatment begins and in the case of nasal complaints, medication should not be started. If severe ulceration of the nasal mucosa occurs (e.g. penetration below the mucosa or association with heavy bleeding), calcitonin (salmon) nasal spray should be discontinued. In case of mild ulceration, medication is to be interrupted temporarily until healing occurs.

Because calcitonin is a peptide, the possibility of systemic allergic reactions exists and allergic type reactions including isolated cases of anaphylactic shock have been reported in patients receiving calcitonin (salmon) nasal spray. In patients with suspected sensitivity to calcitonin, skin testing should be considered prior to treatment. Allergic reactions should be differentiated from generalized flushing and hypotension.

The excipient benzalkonium chloride solution is an irritant and may cause irritation of the nasal mucosa.

Calcitonin (salmon) nasal spray may cause transient dizziness, which may impair the reaction of the patient. Patients must therefore be warned that transient dizziness may occur in which case they should not drive or use machines.

Drug Interactions

No drug interactions with intranasal calcitonin (salmon) have been reported.

Undesirable Effects

Local

Very common (>10%): rhinitis (including dry nose, nasal edema, nasal congestion, sneezing, allergic rhinitis), unspecified symptoms of the nose (e.g. soreness, papules, musty odour, irritation, erythema, excoriation).

Common (>1% to < 10%): ulcerative rhinitis, sinusitis, epistaxis

These events are generally mild (in about 80% of reports) and require discontinuation of the treatment in less than 5% of cases.

Incidence of nasal adverse events (rhinitis, irritation, erythema, and excoriation) was found to be higher in patients older than 65 years and especially among those aged 75 years and older compared with patients younger than 65 years.

Systemic Undesirable Effects

Common (>1% to <10%): flushing, dizziness, headache, nausea, diarrhoea, abdominal pain, musculoskeletal pain, pharyngitis, fatigue, taste perversions.

Uncommon (>0.1% to <1%): hypertension, vomiting, arthralgia, coughing, influenza-like symptoms, oedema (extremities and generalised), abnormal vision.

Calcinase nasal spray may give rise to hypersensitivity reactions such as generalised skin reactions, flushing, oedema (facial, extremities and generalised), hypertension, arthralgia and pruritus. Allergic and anaphylactoid like reactions and single cases of anaphylactic shock have been reported.

Overdose

No instances of overdose with calcitonin (salmon) nasal spray have been reported and no serious adverse reactions have been associated with high doses. There is no known potential for drug abuse for calcitonin (salmon). Nausea, vomiting, flushing and dizziness are known to be dose dependent when calcitonin is administered parenterally. Such events might therefore also be expected to occur in association with an overdose of calcitonin (salmon) nasal spray. However, calcitonin (salmon) nasal spray has been administered up to 1600 IU as a single dose and up to 800 IU per day for three days without causing any serious adverse event. If symptoms of overdose appear, treatment is to be symptomatic.

There have been no reports of hypocalcemic tetany. However, the pharmacologic actions of calcitonin (salmon) nasal spray suggest that this could occur in overdose. Therefore, provisions for parenteral administration of calcium should be available for the treatment of overdose.

Pharmacodynamic and Pharmacokinetic Properties

Calcitonin is a polypeptide hormone secreted by the parafollicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish.

Mechanism of Action

Calcitonin acts primarily on bone, but direct renal effects and actions on the gastrointestinal tract are recognized. Calcitonin (salmon) appears to have actions essentially identical to calcitonins of mammalian origin, but its potency per mg is greater and it has a longer duration of action.

The actions of calcitonin on bone and its role in normal human bone physiology are still not completely elucidated, although calcitonin receptors have been discovered in osteoclasts and osteoblasts. Calcitonin is a calciotropic hormone, which inhibits bone resorption by a direct action on osteoclasts. By inhibiting osteoclast activity via its specific receptors, calcitonin (salmon) decreases bone resorption. Calcitonin markedly reduces bone turnover in conditions with an increased rate of bone resorption such as osteoporosis.

The absence of mineralisation defect with calcitonin has been demonstrated by bone histomorphometric studies both in man and in animals.

In pharmacological studies, calcitonin has been shown to have analgesic activity in animal models. Intranasal calcitonin produces a clinically relevant biological response in humans after only a single dose, as shown by an increase in the urinary excretion of calcium, phosphorus and sodium (by reducing their tubular re-uptake) and a decrease in the urinary excretion of hydroxyproline. Long term administration of intranasal calcitonin significantly suppresses biochemical markers of bone turnover for up to 5 years of treatment.

Calcitonin (salmon) nasal spray results in a statistically significant 1-2% increase in lumbar spine Bone Mineral Density (BMD) which is evident from year 1 and is sustained for up to 5 years. Hip BMD is preserved.

Pahrmacokinetics

Pharmacokinetic parameters of intranasally administered calcitonin (salmon) are difficult to quantitate due to the inadequate sensitivity and uncertain specificity of the available immunoassay methods used in the studies. The bioavailability of a 200 IU dose relative to parenteral administration is between 2 and 15%. Calcitonin (salmon) nasal spray is absorbed rapidly through the nasal mucosa and peak plasma concentrations are attained within the first hour of administration. The half life of elimination of calcitonin (salmon) has been calculated to be approximately 16 to 43 minutes. There is no evidence of accumulation of the drug observed on repeated nasal administration at 10 hour intervals for up to 15 days. Doses higher than the recommended dose result in higher blood levels (as shown by an increase in AUC) but relative bioavailability does not increase. As is the case with other polypeptide hormones, there is very little value in monitoring plasma levels of calcitonin (salmon) since these are not directly predictive of the therapeutic response. Hence, calcitonin activity is to be evaluated by using clinical parameters of efficacy. Plasma protein binding is 30 to 40%.

Shelf life

24 months

Packaging Information

Calcinase is available in vial of 30 Metered Doses

Storage and Handling Instructions

Store unopened bottle in refrigerator at a temperature between 2°C and 8°C. Protect from freezing. Once opened the bottle may be stored at room temperature below 25°C in an upright position for upto 4 weeks.

The protective cap should be on the bottle whenever it is not in use.