Drugs affecting calcium balance

Preparations of calcium S.No Preparation Characteristic

1 Calcium chloride

27 % calcium , highly irritant , not for IM use. Orally also irritable

2 Calcium gluconate

9 % calcium , non irritating Sense of warmth produced on injection

3 Calcium lactate 13 % calcium, orally well tolerated , non irritating

4 Calcium dibasic phosphate

23 % calcium , used as antacid and calcium supplement

5 Calcium carbonate

40 % calcium , tasteless, non irritating , used as antacid

Uses of calcium

• Tetany • As dietary supplement • Osteoporosis • Empirical: – dermatoses, parasthesias, weakness, vague

complaints • As antacid • Lead colic, hypermagnesemia, hyperkalemia • Cardiac arrest

Treatment of hypercalcemia • Hydration & dietary calcium restriction < 400 mg/day • Sodium chloride:• Saline administration will cause renal elimination

of calcium • Furosemide 20 -40 mg every 2-4 hrs • Glucocorticoids: reduce intestinal absorption &

tubular reabsorption of calcium • Calcitonin: 4 IU/kg SC OR IM twice or once daily can

be increased to 8 IU/kg IM 6 hrly • Mithramycin : 25 μg/kg IV over period of 4- 6 Hrs • Inorganic phosphate: phosphosoda 5 ml TDS

Preparations of calcitonin

• Porcine (Natural) calcitonin:• Antigenic

• Synthetic salmon calcitonin:• More potent due to slower metabolism

• Synthetic human calcitonin:• 1 IU = 4 μg of std preparation

• Calcitonin is given by SC/IM routes. Salmon calcitonin is also available as nasal spray

Uses of calcitonin

• Hypercalcemia states (e.g associated with neoplasia)

• Pagets disease of bone: • Postmenopausal osteoporosis & corticosteroid

induced osteoporosis:• Salmon calcitonin is used as nasal spray along with

Vit D supplements 200 IU /day

Preparations of vit D

• Ergocalciferol: Vit D2 oral capsules• Cholecalciferol: Vit D3• Oral/IM injection 3-6 lac IU every 2-6 month interval

• Calcitriol: oral capsules & solution 0.25-1 μg daily or IV on alternate days

• Alfacalcidiol & dihydrotachysterol: • Prodrugs orally effective and rapidly biotransformed

into calcitriol in liver. They are effective in renal bone disease & hypoparathyroidism

• Calcipotriol : Vitamin D analog used topically in psoriasis

Uses of Vit D 1. Prophylaxis: 400 IU/day and treatment 3000 -4000 IU/day

of rickets & osteomalacia alternatively Oral/IM injection 3-6 lac IU every 2-6 month interval

2. Metabolic rickets : 1. Vit D resistant rickets: high doses 2. Vit D dependent rickets: calcitriol or alphacalcidiol 3. Renal rickets: calcitriol or alphacalcidiol

3. Senile or post menopausal osteoporosis 4. Hypoparathyroidism : calcitriol or alphacalcidiol are better 5. Fanconis syndrome: Vit D can raise lowered phosphate

levels that occur in this condition 6. Calcipotriol : Vitamin D analog used topically in psoriasis

Vitamin D deficiency

•Deficiency of vitamin D leads to: Rickets in small children.

Osteoporosis

Clinical manifestation1. Osseous changes: 1) Head: craniotabes, frontal bossing, box like skull,

delayed closure of anterior fontanelle 2) Teeth: delayed eruption, with abnormal order 3) Chest: rachitic rosary, pigeon chest, funnel-shaped

chest 4) Spinal column: scoliosis,kyphosis, and lordosis 5) Extremities: bowlegs 6) Rachitic dwarfism2. Muscular system: potbelly, late in standing and walking3. Motor development: delayed

4. Other nervous and mental symptoms

Treatment1. Food and nursing care2. Prevention of complications3. Special therapy 1) Vitamin D therapy A. General method Vitamin D 2000-4000IU/day for 2-4 weeks, then change to

preventive dosage (400IU). B. A single large dose: For severe case, or Rickets with complication, or those who

can’t bear oral therapy. Vitamin D3 3 LAC -6 LAC IU, im, preventive dosage can be used after 2-6 months.

Prevention1. pregnant and lactating women should take

adequate amount of vitamin D.2. Advocate sunbathing3.Advocate breast feeding, give supplementary food

on time4. Vitamin D supplementation:• In prematures, twins & weak babies: 800 IU/day• For term babies and infants : 400 IU per day,• For those babies who can’t maintain a daily

supplementation: Vitamin D3 1L-2L IU IM.

5. Calcium supplementation:

Vitamin D - Sources

• Sunlight is the most important source

• Not found naturally in many foods• Synthesized in body• Plants (ergosterol)

– Sun-cured forages• Fluid milk products are fortified

with vitamin D• Oily fish & Fish liver oil• Egg yolk• Butter• Liver• Difficult for vegetarians

TOXICITY•Hypervitaminosis D causes hypercalcemia, which manifest as:• Nausea & vomiting• Excessive thirst , polyuria & anorexia • Severe itching• Joint & muscle pains• Disorientation & coma.• Calcification of soft tissue– Lungs, heart, blood vessels ,

• Hypercalcemia – Normal is ~ 10 mg/dl– Excess blood calcium leads to stone formation in

kidneys

Biphosphonates • Analogs of pyrophosphate

• First generation: • Etidronate

• Second generation: • Pamidronate • Alendronate

• Third generation :• Risedronate • Zoledronate

• Mechanism of action

Protect dissolution of hydroxyapatite from bone

Accelerates apoptosis of osteoclasts

Inhibits release of IL-6

• Highly polar so less poorly absorbed through GIT • Part of absorbed drug is incorporated into bone &

remains for long periods years to months • The free drug is excreted unchanged in urine

• Pharmacokinetics

Biphosphonates uses and adverse effects • Uses • Pagets disease of bone: treatment of choice • For prevention and treatment of post-menopausal

osteoporosis • To prevent corticosteroid induced osteoporosis along with

calcium carbonate • Hypercalcemia of malignancy: Zolendronate • Control hypercalcemia of hyperparathyroidism• To relieve pain of lytic bone lesions

• Nausea, vomiting diarrhoea, esophagitis, peptic ulcer, fever, myalgia, hypocalcemia, headache & skin rashes

• OSTEONECROSIS , renal impairment

• Adverse effects

Osteoporosis

Osteoporosis

• A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.

Primary osteoporosis

• Postmenopausal– ↓ estrogen results in ↑ osteoclastic activity

without ↑ osteoblastic activity– Bone loss – 2-3% per year of total bone mass– Most common fx: vertebral, distal forearm

• Age related – – 3rd decade of life starts slow decline in bone mass

at rate of 0.5-1% per year– Most common types of fx: hip and radius, F>M

Secondary OsteoporosisDisease states

Acromegaly Addison’s disease Amyloidosis Anorexia COPD Hemochromatosis Hyperparathyroidism Lymphoma and leukemia Malabsorption states

Multiple myeloma Multiple sclerosis Rheumatoid arthritis Sarcoidosis Severe liver dz, esp. PBC Thalessemia Thyrotoxicosis

Drugs causing osteoporosis

AluminumAnticonvulsantsExcessive thyroxineGlucocorticoidsGnRH agonistsHeparinLithium

Normal Bone Remodeling: A Balance of Bone Resorption and Formation

2–4 weeks2–4 weeks 3–4 months3–4 months

Resting Stage Formation Remodeling

CompletedActivation Resorption

Lining cells

Osteoclast precursors

Osteoclasts Osteoblasts

Bone remodeling unit

Lining cells

FormationResorption

Secondary mineralization

Osteoporosis: Resorption Exceeds Formation

2–4 weeks2–4 weeks 3–4 months3–4 months

Lining cellsOsteoclast precursors

Bone remodeling unit

1. Adapted from: Rosen CJ. Available at: http://www.endotext.org/parathyroid/index.htm. Accessed December 7,2007.

Lining cells

OsteoclastsOsteoblasts

FormationResorption

Pits develop that weaken bone

Resting Stage Formation Remodeling

CompletedActivation Resorption Secondary

Mineralization

Treatment Objectives

29

Osteoclast

Inhibition of resorption

Osteoblast

Stimulation of formation

Osteoporosis drugs used

Anabolic Agent Antiresorptive AgentsFunction Forms new bone Suppresses bone resorption

Mechanism ↑s osteoblast activity ↓ osteoclast activity

Bone turnover

Accelerates turnover Slows turnover

BMD effect Forms new bone ↑ bone volume

↑ mineralization of existing bone

Drugs Teriparatide , Fluoride, Androgens

Bisphosphonates Calcitonin , ERT,SERMs, Calcium,VitD ,Thiazides

Dual action bone agent :Strontium ranelate

Antiresorptive Agents

Bisphosphonates

• Etidronate • Pamidronate• Alendronate • Risedronate • Ibandronate • Tiludronate• Zoledronate

Bisphosphonates

Advantages Increases BMD by 1-4%,

decreases fracture risk by 41-44%

No increased risk of breast, uterine ca or thromboembolic events

Weekly dosing

DisadvantagesRisk of gastrointestinal sxex dosing instructionsContraindicated in ESRD;

need to adjust dose according to creatinine clearance

Estrogen Replacement Therapy (ERT)

Indication: Used to prevent and treat osteoporosis (FDA indication is for prevention)

Mechanism: ↓es osteoclast activity, Acts on osteoblast to ↓ production of IL- 6 ↑ production of osteoprotegerin,there by interfering

with recruitment of osteoclast precursors.Dose: Estrogen: 0.625mg od, Progesterone 2.5mg

qd (if uterus present)

ERT Advantages

Increases bone density (1-5%) and decreases risk of fracture (25%)

Relief of hot flashes, vaginal dryness

Decreases LDL, increases HDL

?Prevention of Alzheimer’s disease

Relatively inexpensive

Disadvantages ↑ bone loss after stopping↑ risk of uterine ca ↑ risk of thromboembolic

eventsPossible ↑ risk of breast

cancer Side effects:

breast tenderness, breakthrough bleeding

↑ risk of coronary events in women with known CAD in first year of use (HERS trial)

Selective Estrogen Receptor Modulators (SERMs)

1.Raloxifene: partial agonist in bone and CVS but an antagonist in endometrium and breast. 2.Tamoxifen: antagonist in breast carcinoma cells, blood vessels but agonist in uterus, bone, liver and pitutary

Dose: Raloxifene 60mg od

SERMS

Advantages Increases bone density

(2%) and decreases fracture risk (30%)

No stimulation of breast or endometrial tissue

No need for progestin in women with uterus

Decrease LDL

Disadvantages Increased risk of

thromboembolic eventsDoesn’t treat post-

menopausal sxMay increase hot flashes

Vitamin D

• It may improve intestinal calcium absorption ,suppress bone remodeling and improve BMD in individuals with marginal or deficient Vit D status.

• Calcitriol – suppresses the PTH function and reduce bone turnover.

• Dosage: 400-800 IU /day.

Thiazide diuretics

• Reduce urinary calcium excretion and constrain bone loss in patients with hypercalciuria.

• Dosage : Hydrochlorothiazide – 25 mg once or twice

daily.

Bone forming agents

rParathyroid hormone [rPTH(1-34), teriparatide]

Mechanism of action: Stimulates new bone formation on trabecular and

cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity.

• Daily SC injections of 40mcg of rPTH for 12-18 months , increased BMD by 9-13% and decreased risk of vertebral fractures by 65 to 69 %

• Side effects: Occasional headache and nausea

Strontium ranelate • Oral strontium ranelate is an alternative oral

treatment, belonging to a class of drugs called "dual action bone agents" (DABAs).

• Proven efficacy, especially in the prevention of vertebral fracture.

• Mechanism of action: ↑collagen & noncollagen protein systhesis, enhances preosteoblast differentiation, ↓ osteoclast function

• Dosage : 2 g oral suspension daily• Adverse effects : thromboembolism

Glucocorticoid-Induced Osteoporosis: Treatment

• Only bisphosphonates have been demonstrated in large clinical trials to reduce the risk of fractures in patients being treated with glucocorticoids.

• Risedronate prevents bone loss and reduces vertebral fracture risk by ~70%. Similar beneficial effects are observed in studies of alendronate.

• Controlled trials of hormone therapy have shown bone-sparing effects, and calcitonin also has some protective effect in the spine.

• Thiazides reduce urine calcium loss, but their role in prevention of fractures is unclear.

• PTH has also been studied in a small group of women with glucocorticoid-induced osteoporosis, where bone mass increased substantially, and teriparatide is currently being investigated in a larger multicenter trial.

Investigational Agents

• Ospemifene, Lasofoxifene • Bazedoxifene• Arzoxifene• Strontium ranelate– Increases collagen & noncollagen protein

synthesis, enhances preosteoblast differentiation, reduces osteoclast function

• Denosumab–Human mAb, inhibits RANKL which inhibits

osteoclast activation and survival

• A human monoclonal antibody to the receptor activator of NFkB

ligand (RANKL), which is given subcutaneously once every six

monthsOral calciomimetic drugs that stimulate intermittent production of parathyroid hormoneSelective oestrogen receptor modulators with mixed oestrogenic and anti-oestrogenic effectsInhibitors of sclerostin, a protein produced by bone that is a negative regulator of bone formation, and its signalling pathway

• Investigation of the causes and management of poor compliance and persistence

• Assessment of the long term effects of anti-resorptive treatments on bone strength

Ongoing research

Thank You.