Department of Orthopedics Khon Kaen University, Khon Kaen, Thailand Miacalcic differentiation value by relieve bone pain & high safety profile Dr. Suppasin Soontrapa Department of Orthopedics Khon Kaen University, Khon Kaen, Thailand 31 July 2010

Synthetic Salmon Calcitonin consisting of 32 amino acids which is the most potent of all calcitonins

Prevent Recurrence of Osteoporotic Fractures Am J Med. 2000 Sep; 109(4):267-76. P.R.O.O.F. Prevent Recurrence of Osteoporotic Fractures A Multicentered, Double-Blind, Randomized, 5-Year Study to Investigate the Efficacy of Salmon Calcitonin Nasal Spray in the Prevention of Osteoporotic Vertebral Fractures Final Analysis Chesnut CH 3rd, Silverman S, Andriano K, Genant H, Gimona A, Harris S, Kiel D, LeBoff M, Maricic M, Miller P, Moniz C, Peacock M, Richardson P, Watts N, Baylink D. 1 1 1

conclusion 200 IU of salmon calcitonin nasal spray per day significantly reduces the risk of new vertebral fracture by 33% to 36% in postmenopausal women with low bone mass or prevalent vertebral fractures.

% Increase in Vertebral BMD % Decrease in Vertebral Fracture Risk Positive Bone Former/ Antiresorptive Agent % Increase in Vertebral BMD % Decrease in Vertebral Fracture Risk Fluoride1 Calcitonin-salmon2 Raloxifene3 Risedronate4 Alendronate5 35 1– 1. 5 2– 3 3– 5 6– 8 36 30 41 47 Per protocol 1. Riggs BL et al. N Engl J Med. 1990;322:802-809. 2. Chesnut CH III et al. Am J Med. 2000;109:267-276. 3. Ettinger B et al. JAMA. 1999;282:637-645. 4. Harris ST et al. JAMA. 1999;282:1344-1352. 5. Black DM et al. Lancet. 1996;348:1535-1541. 2

ข้อน่าสังเกตจากการเปรียบเทียบข้างต้น น่าจะมีสิ่งอื่นนอกจากความหนาแน่นของกระดูกที่ช่วยให้กระดูกแข็งแรงขึ้น Bone Quality

(QUalitative Effects of Salmon Calcitonin Therapy) The QUEST study (QUalitative Effects of Salmon Calcitonin Therapy)

Conclusion CT-NS 200 IU พ่นจมูกทุกวันเป็นเวลา 2 ปีในสตรีหลังหมดประจำเดือนที่เป็นโรคกระดูกพรุน สามารถเพิ่มหรือคงสภาพของ trabecular microarchitecture ของกระดูก distal radius เมื่อเทียบกับก่อนรักษา ในขณะที่ยาลวงมีแนวโน้มลดลง

Calcitonin & Pain 21 Jan 09

Objective To assess the effects of calcitonin vs. placebo for the treatment of acute pain in patients sustaining stable, recent, osteoporotic vertebral compression fractures

1989 100 IU IM 1991 100 IU IM 1997 200 IU IN

1999 200 IU suppo. 1989 100 IU BID of IN

results The combined results from five randomized controlled trials, involving 246 patients Calcitonin significantly reduced the severity of pain using a visual analogue scale following diagnosis Pain at rest was reduced as early as 1 week into treatment (weighted mean difference [WMD] =3.08; 95% confidence interval [CI]: 2.64, 3.52)

results The effect on pain continued weekly to 4 weeks (WMD =4.03; 95% CI: 3.70, 4.35). A similar pattern was seen for pain scores associated with sitting, standing, and walking.

Subgroup analysis The VAS (sitting) IN calcitonin, WMD 2.55 (95% CI: 2.16, 2.84) calcitonin rectal suppositories, WMD 2.00 (95% CI: 1.46, 2.54) IM calcitonin, WMD 4.00 (95% CI: 3.0, 5.0) IM calcitonin (n =28) better pain control and were able to mobilize more quickly than intra-nasally (IN) or rectal suppository

Side effects All in mild and were not significant difference

Conclusion Calcitonin appears to be effective in the management of acute pain associated with acute osteoporotic vertebral compression fractures by shortening time to mobilization

pain after a vertebral fracture The location of the pain is dependent on the location of the vertebral fractures can be confirmed radiographically. Pain is exacerbated by weight-bearing activities Valsalva maneuvers, lifting and bending, Tenderness to percussion.

Goals of Pain Treatment Improvement in pain symptoms Restoration of function

Multidisciplinary Pain Management Approach Goal-oriented exercise regimen Appropriate lifestyle modifications Pain relief modalities Psychosocial support Various assistive devices

Mechanism of Pain & Pain Pathway

postsynaptic neurone interneurone presynaptic neurone lateral STT

The Somatosensory System Somatosensory cortex Frontal cortex Thalamus Hypothalamus Descending pathway Ascending tracts Periaqueductal gray matter Midbrain Medulla interneurone Dorsal horn area Spinal cord Noxious stimuli activate receptors in periphery

Effect of Calcitonin in the CNS Periaqueductal gray ถือเป็นศูนย์ควบคุมความรู้สึกปวดที่สำคัญ พบมี calcitonin receptor ที่บริเวณนี้มาก เมื่อจับกับ calcitonin จึงมีผลระงับอาการปวดได้

The Antinociceptive Effects of calcitonin Opioidergic transmission Serotonergic transmission Guidobono F, et al., Role of catecholamines in calcitonin-induced analgesia. Pharmacology 31:342-8 (1985) Maeda Y, et al., Neuronal mechanism of the inhibitory effect of calcitonin on N-methyl-D-asparatate induced aversive behavior. Eur J Pharmacol 275: 163-70 (1995)

สารต่างๆที่ถูกหลั่งออกมาจากเซลล์หลายๆชนิดภายหลังได้รับบาดเจ็บ จะมีส่วนทำให้เกิด peripheral sensitization โดยการอักเสบทำให้มีการหลั่งสารเคมีมากมายจาก mast cells, macrophages, immune cells, and injured cells ซึ่งอาจออกฤทธิ์โดยตรงหรือโดยทางอ้อมเพื่อเปลี่ยนความไวของปลายประสาทในการตอบสนองต่อการกระตุ้น ASIC = acid-sensing ion channel CRH = corticotrophin-releasing hormone GIRK = G-protein-coupled inward rectifying potassium channel iGluR = ionotropic glutamate receptor IL-1b = interleukin-1beta mGluR = metabotropic glutamate receptor NGF = nerve growth factor PAF = platelet-activating factor PGE2= prostaglandin E2 PKA = protein kinase A PKC = protein kinase C SSTR2A = somatostatic receptor 2A TNF-alpha = tumor necrosis factgor-a TrKA = tyrosine kinase receptor A TTXr = tetrodoxin-resistant sodium channel Mu = mu-opioid receptor M2 muscarinic 5HT = serotonin LIF = leukocyte inhibit factor serotonin

The Antinociceptive Effects of calcitonin Opioidergic transmission Serotonergic transmission Guidobono F, et al., Role of catecholamines in calcitonin-induced analgesia. Pharmacology 31:342-8 (1985) Maeda Y, et al., Neuronal mechanism of the inhibitory effect of calcitonin on N-methyl-D-asparatate induced aversive behavior. Eur J Pharmacol 275: 163-70 (1995)

Mechanism of Action in Animal Models Most evidence indicates that calcitonin has a direct effect on the central nervous system (CNS) for acute pain that is independent of opioid action. In the rabbit dental pulp model, the analgesia subsequent to salmon1 or porcine2 calcitonin administration was not reversed by the opioid antagonist naloxone. 1Braga P, et al. Lack of opiate receptor involvement in centrally induced calcitonin analgesia. Life Sci 1978;22:971-7. 2Yamamoto M, et al. Effect of porcine calcitonin on behavioural and electrophysiological responses elicited by electrical stimulation of the tooth pulp in rabbits. Pharmacology 1982;24:337-45.

Mechanism of Action in Animal Models SCT and morphine (which acts on m-opioid receptors) acted in an additive manner. In vitro assays suggested that calcitonin potentiates the action of ligands acting on d- and k-opioid receptors, but not on m-opioid receptors.1 1Martin MI, et al. Analgesic effect of two calcitonins and in vitro interaction with opioids. Gen Pharmacol 1995;26:641-7.

The Antinociceptive Effects of calcitonin Opioidergic transmission Serotonergic transmission Guidobono F, et al., Role of catecholamines in calcitonin-induced analgesia. Pharmacology 31:342-8 (1985) Maeda Y, et al., Neuronal mechanism of the inhibitory effect of calcitonin on N-methyl-D-asparatate induced aversive behavior. Eur J Pharmacol 275: 163-70 (1995)

FIG. 1. Antinociceptive effects of elcatonin in the tail-withdrawal 1st experiment N=48 12 sham 12: 20 U/kg/d 12: 5 U/kg/d FIG. 1. Antinociceptive effects of elcatonin in the tail-withdrawal test of OVX rats. Thirty-six rats were OVX and 12 were sham operated. Tail-withdrawal latencies were measured once a week. OVX rats were divided into three groups, and vehicle (h), 5 U/kg/day of elcatonin (n) or 20 U/kg/day (j) was injected subcutaneously five times per week. Vehicle was injected to the sham (s). Each value is the mean of 12 data 6 SEM. Significant difference; *p , 0.05, **p , 0.01 vs. sham, ##p , 0.01 vs. vehicle-injected OVX group. OVX 12: placebo 3 4 Operation date

FIG. 1. Antinociceptive effects of elcatonin in the tail-withdrawal 1st experiment N=48 12 sham 12: 20 U/kg/d 12: 5 U/kg/d FIG. 1. Antinociceptive effects of elcatonin in the tail-withdrawal test of OVX rats. Thirty-six rats were OVX and 12 were sham operated. Tail-withdrawal latencies were measured once a week. OVX rats were divided into three groups, and vehicle (h), 5 U/kg/day of elcatonin (n) or 20 U/kg/day (j) was injected subcutaneously five times per week. Vehicle was injected to the sham (s). Each value is the mean of 12 data 6 SEM. Significant difference; *p , 0.05, **p , 0.01 vs. sham, ##p , 0.01 vs. vehicle-injected OVX group. OVX 12: placebo 3 4 Operation date

No serotonin production Inhibitor of serotonin biosynthesis

In Experiment 2, starting 3 weeks after surgery, the first 12 sham 2nd experiment N=48 24: 20 U/kg/d 12: 20 U/kg/d + saline 12: placebo In Experiment 2, starting 3 weeks after surgery, the first and the second OVX group were administered 20 U/kg/day of elcatonin, and the third OVX group and the sham group were injected with vehicle. The second group was intraperitoneally injected with PCPA at 8 weeks after surgery, and the other three groups were injected with saline instead of PCPA. 12: 20 U/kg/d + PCPA 4

(inhibitory neurone)

Ad, C lateral STT postsynaptic neurone interneurone presynaptic neurone lateral STT

(fast fiber) (slow fiber)

(inhibitory neurone)

EPSC = excitatory postsynaptic current

EPSC = excitatory postsynaptic current

Unresponsive to serotonin

Some problem on C-fiber

Calcitonin has some effects on C-fiber

Conclusion การที่ calcitonin สามารถลดอาการปวดในผู้ป่วยโรคกระดูกพรุน โดยกระทำผ่าน serotonin pathway โดยการเพิ่ม receptor ต่อ serotonin ที่ C-fiber ให้กลับมาเป็นปกติ calcitonin จับกับ calcitonin receptor ที่บริเวณ Periaqueductal gray ซึ่งเป็นศูนย์ควบคุมความรู้สึกปวดที่สำคัญใน CNS และกระตุ้นให้มีการหลั่ง serotonin เพิ่มขึ้น เพิ่มฤทธิ์ของสารที่จับกับ d, k opioid receptor

Safety of Calcitonin

Therapeutic options for osteoporosis Inhibitors of bone resorption Bisphosphonates Alendronate Risedronate Ibandronate Zoledronate Calcitonin Estrogen ± progestin Selective estrogen receptor modulators (SERMs) Raloxifene Stimulators of bone formation Parathyroid hormone Mixed mechanism of action Vitamin D and metabolites Vitamin K Strontium ranelate Slide 34 Speaker Notes: Over the last few years, many new therapeutic options have become available for the prevention and treatment of osteoporosis. Commonly used agents include a variety of estrogen and estrogen-plus-progestin preparations, selective estrogen receptor modulators (SERMs) (such as raloxifene), calcitonin, and bisphosphonates (such as etidronate, alendronate, and risedronate). Calcium and vitamin D are recommended for all women at risk for osteoporosis unless there are specific contraindications. Recommended for all women at risk for osteoporosis Calcium and vitamin D

Therapeutic options for osteoporosis Inhibitors of bone resorption Bisphosphonates Alendronate Risedronate Ibandronate Zoledronate Selective estrogen receptor modulators (SERMs) Raloxifene Stimulators of bone formation Parathyroid hormone ใช้ได้เฉพาะในกรณีค่า crcl > 30 cc/min Mixed mechanism of action Strontium ranelate Slide 34 Speaker Notes: Over the last few years, many new therapeutic options have become available for the prevention and treatment of osteoporosis. Commonly used agents include a variety of estrogen and estrogen-plus-progestin preparations, selective estrogen receptor modulators (SERMs) (such as raloxifene), calcitonin, and bisphosphonates (such as etidronate, alendronate, and risedronate). Calcium and vitamin D are recommended for all women at risk for osteoporosis unless there are specific contraindications. Recommended for all women at risk for osteoporosis Calcium and vitamin D

Renal Problem in Thai Elderly Women Community survey of the KK elderly women age > 60 yrs. 1,732 cases (S. Soontrpa, 2003: unpublished data) Mean (SD) = 71.89 (5.51) CrCl < 30 cc/min = 23% One forth of community elderly women with the age > 60 yrs. had severe renal insufficiency

Therapeutic options for osteoporosis Inhibitors of bone resorption Bisphosphonates Alendronate Risedronate Ibandronate Zoledronate Calcitonin Estrogen ± progestin Selective estrogen receptor modulators (SERMs) Raloxifene Stimulators of bone formation Parathyroid hormone Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcer Mixed mechanism of action Vitamin D and metabolites Vitamin K Strontium ranelate Slide 34 Speaker Notes: Over the last few years, many new therapeutic options have become available for the prevention and treatment of osteoporosis. Commonly used agents include a variety of estrogen and estrogen-plus-progestin preparations, selective estrogen receptor modulators (SERMs) (such as raloxifene), calcitonin, and bisphosphonates (such as etidronate, alendronate, and risedronate). Calcium and vitamin D are recommended for all women at risk for osteoporosis unless there are specific contraindications. Recommended for all women at risk for osteoporosis Calcium and vitamin D

Calcitonin Renal Actions Increases in calcium, phosphorus and sodium excretion Inhibits phosphate reabsorption by the kidney tubules1 Calcitonin inhibits tubular reabsorption of Ca2+, leading to increased rates of its loss in urine.1 Stimulation of 25-(OH)D3-1-α-hydroxylase activity 2 Hormone binding site in renal cortical brush border and basolateral membranes 2 Basolateral membrane binding follows with activation of adenylate cyclase Brush border membrane binding is related to metabolism of calcitonin 3 Carney SL. Miner Electrolyte Metab (1997) 23 (1): 43–7. Kurokawa K, in Seldin DW, Giebisch G. The Kidney: Physiology and Pathophysiology. New York: Raven 1985 Rabkin R, Kitaji J. Mineral Electrolyte Metab (1983) 9: 212-226 | Cycle Meeting | NP | 08072010 | Renal Safety | Confidential | Cycle Meeting | NP | 08072010 | Renal Safety | Confidential

Calcitonin Renal Metabolism Renal metabolism accounts for approximately 2/3 of the total metabolism of calcitonin1 Removal of calcitonin from renal circulation by Glomerular filtration followed by proximal tubular degradation by hydrolysis after contact with brush-border membrane (40%) Receptor-mediated, filtration-independent removal from the postglomerular peritubular circulation Basolateral endocytosis with intracellular degradation Basolateral membrane hydrolysis in more distal nephron segments 2 Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically-inactive fragments of the molecule. 3 The metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. The clinical relevance of this finding is not known. 3 Ardaillou R., Paillard F., Savier C., Bernier A. Rev Eur Etud Clin Biol (1971) 16: 1031-1036 Simmons RE, et. al. Am J Physiol Renal Physiol (1988) 254 (4): 593-599 Electronic Medicines Compendium". http://emc.medicines.org.uk/. Retrieved 2008-08-07.  | Cycle Meeting | NP | 08072010 | Renal Safety | Confidential | Cycle Meeting | NP | 08072010 | Renal Safety | Confidential

Comparison of Bisphosphonates and Calcitonin Renal Tolerability Biologically-active in kidney All biologically-active Rapidly degraded to non-active metabolites Induced renal cell apoptosis Yes No Type of renal pathology Acute Tubular Necrosis | Cycle Meeting | NP | 08072010 | Renal Safety | Confidential | Cycle Meeting | NP | 08072010 | Renal Safety | Confidential

Prevent Recurrence of Osteoporotic Fractures Am J Med. 2000 Sep; 109(4):267-76. P.R.O.O.F. Prevent Recurrence of Osteoporotic Fractures A Multicentered, Double-Blind, Randomized, 5-Year Study to Investigate the Efficacy of Salmon Calcitonin Nasal Spray in the Prevention of Osteoporotic Vertebral Fractures Final Analysis Chesnut CH 3rd, Silverman S, Andriano K, Genant H, Gimona A, Harris S, Kiel D, LeBoff M, Maricic M, Miller P, Moniz C, Peacock M, Richardson P, Watts N, Baylink D. 1 1 1

Adverse Effects Rhinitis (nasal congestion, nasal discharge, or sneezing) occurred in active-treated groups higher than in placebo group (22% vs 15%; p<0.01) Most of them were mild to moderate severity, (calcitonin: 67% mild, 30% moderate; placebo: 64% mild, 27% moderate)

Key Advantage of Miacalcic Nasal Spray Easy to use : a simple dose a day Convenience : any time…….anywhere Patients need not to be in standing position Can be taken with food, milk and other medications No contraindications for patients with GI problems Renal problems Limited mobility No risk of reflux esophagitis, esophageal ulcer

Thank you