Calcium and PTH and osteoporosis

1. Osteoporosis
&
Management
Basic & applied Pharmacology

2. The human skeleton undergoes a continuous
process of remodelling throughout life—some
bone being resorbed and new bone being laid
down resulting in the complete skeleton being
replaced every 10 years.

3. • The human skeleton consists of 80% cortical
bone and 20% trabecular bone.
• Cortical bone is the dense, compact outer
part, and trabecular bone the inner
meshwork.
• Trabecular bone, having a large surface area, is
metabolically more active and more affected
by factors that lead to bone loss.

4. • The main minerals in bone are calcium and
phosphates.
• More than 99% of the calcium in the body is in
the skeleton, mostly as crystalline
hydroxyapatite.
• The main cells in bone homeostasis are
osteoblasts, osteoclasts and osteocytes.

5. • Osteoblasts are bone-forming cells derived
from precursor cells in the bone marrow and
the periosteum:

6. CALCIUM

7. Physiological role of Ca+2
 Coagulation,
 Nerve - muscle excitation & contraction,
 Sec. messenger,
 Bone & teeth,
 Regulation
- Endogenous: by PTH, Calcitonin, calcitriol
(active Vit D)
- Exogenous: by Ca+2 supplements,
biphosphonates & thiazides

9. Uses
• Tetany 10-20ml Ca+2 gluconate IV followed by
infusion(50-100 ml)
• Supplement in fractures, growing child, pregnancy
• Osteoporosis: Ca+2 plus vit D3 and / or HRT, Raloxifen,
bisphosphonates & Calcitonin
• As placebo & antacid: Ca+2 Carbonate, Ca+2 dibasic
phosphate
• S/E : Constipation, ectopic deposits
• D/I : Phytate, PO4, oxalate, tetracycline ,Phenytoin &
Glucocorticoids reduce Ca+2 absorption
• Ca+2 is absorbed in GIT by facilitated diffusion & by
active transport under influence of Vit D

10. Parathyroid hormone (PTH)
• Parathyroid hormone is secreted by
parathyroid glands.
• The secretion of parathyroid hormone is
regulated by the plasma calcium levels. The
PTH has a role in maintaining the calcium
levels.
• Low plasma calcium levels stimulates the PTH
secretion, whereas high calcium levels inhibit
its secretion.
• Prolonged hypocalcemia causes hypertrophy

11. PTH Actions
↑ plasma Ca+2
↑ resorption of Ca+2 from bones-
↑ Ca+2 reabsorption from DCT
↑ GIT formation of Vit D
↑ Proliferation & differentiation
of pre osteoblasts & deposition
of osteoid

12. MOA of PTH
Binding to PTH receptor (osteoblast)→ G
protein → ↑ RANKL → bind RANK of
osteoclast precursor & activate them→
remodeling pit formation →increased
osteoclastic activity
Regulation:
Fall in plasma Ca+2 → ↑ PTH release through
cyclic AMP & activation of protein kinase C

13. osteoprotegerin (OPG)

15. Uses
 PTH not used in hypoparathyroidism → use Ca+2 & vit
D
Teriparatide
• recombinant PTH, subcuteaneous daily
• Rx of severe osteoporosis
• Stimulate bone formation
• Diagnostic: Give IV if plasma Ca+2 ↑ then it is true
hypoparathyroidism
 Cinacalcet
→ ↓ PTH secretion
- Rx of secondary hyperparathyroidism due to renal
disease
- Rx of parathyroid tumor

16. CALCITONIN
 Parafollicular C cells of thyroid
 Hypocalcaemic hormone opposite of PTH
 ↑ plasma Ca+2 → ↑ calcitonin release
 Inhibit bone resorption by action on
osteoclast
 Inhibit PCT Ca+2 & PO4 reabsorption
 Action through G protein coupled receptor
→ ↑ cyclic AMP

17. CALCITONIN Contd.
 Preparation
- Salmon calcitonin → IM, SC 100 IU
- Human calcitonin also used
- Nasal spray available
- Longer use → resistance develop

18. Uses
Hypercalcaemia- 4-8 IU/Kg 6-12 hrly X 2days
initially ( faster acting ) only as supplement to
BPN.
Post menopausal osteoporosis- 100 IU SC or
IM daily with Ca+2 and vit D → ↑ bone
mineral density
Paget’s disease- 100 IU daily or alternate day
X 2-3 months. Bisphosphonates are preferred

19. Vit D
 It is regarded as hormone
 Active forms
- 1, 25 (OH)2 D3 → calcitriol (from 7 dehydrocholesterol-
skin)
- 1, 25 (OH)2 D2 ( from ergosterol – yeast, bread, milk)
- activation by sunlight (UV), liver & finally kidney
 Actions
- ↑ GIT absorption of Ca+2 (increase calcium channels &
Calbindin ), PO4 → ↑ Pl. Ca+2
- Promote recruitment & differentiation of osteoclast → ↑
bone resorption
- Induce RANKL (Osteoblast) → activate osteoclast & lays
osteoid ( osteoblast ).
- ↑ renal tubular reabsorption of Ca+2 & PO4

21. MOA
 Combine with cytoplasmic Vit D receptor →
translocate to nucleus → ↑ synthesis of mRNA
→ regulation of protein synthesis
 Also causes endocytic capture of Ca+2 in GIT
 Vit D deficiency
- ↓ pl. Ca+2 → ↑ PTH → ↑ bone resorption
causes rickets in child & osteomalacia in adult
- in osteoporosis bone matrix is also affected
 Hypervitaminosis
- if dose > 50,000 IU/day can cause ↑ pl. Ca+2 ,
ectopic depositions and ↓ linear growth in child
- Rx with glucocorticoids & of hypercalcaemia,

22. Pharmacokinetics & Uses
 Bile necessary for GIT absorption → lymphatics
→ bound to plasma proteins or storage in
adipose tissue → metabolized in liver, long t ½
→ excreted in bile
 Uses
- Calcitriol mainly used
1. Rickets, osteomalacia Rx 4000 IU/ day
- Prophylaxis in obstructive jaundice &
steatorrhoea 400 IU/day
- Rickets can be due to deficiency of Vit D,
metabolic rickets or renal rickets → use
calcitriol

23. Uses Contd.
2. Osteoporosis → senile & postmenopausal
3. Hypoparathyroidism → 50000 IU/day
4. Fanconi syndrome → ↑ PO4
- Due to outdated tetracycline
5. Calcipotriol (do not ↑ pl. Ca+2) → plaque
psoriasis, skin cancer, immunological disorder
 D/I
- Cholestyramine & liq. Paraffin ↓ vit D abs.
- Phenytoin & Phenobarbitone ↓
responsiveness of target tissue to vit D

24. Preparations
 Calciferol Vit D2
 Cholacalciferol (non active Vit D3)
 Calcitriol active Vit D3
 Alfa calcidiol (prodrug)
 Dihydrotachysterol (synthetic Vit D2)

25. Bisphosphonates
• These agents are analogues of
pyrophosphate and they inhibit the bone
resorption.
• These are the most effective antiresorptive
drugs useful in preventing osteoporosis and
treating hypercalcemia & metabolic bone
diseases.

26. Three generations
Generations Potency Drugs
1st generation
Bisphosphonates
Least potent  Etidronate
 Tiludronate
2nd generation
Bisphosphonates
10-100 times
more potent than
1st gen.
 Alendronate
 Pamidronate
 Ibandronate
3rd generation
Bisphosphonates
10,000 times
more potent than
2nd gen.
 Risedronate
 Zoledronate

27. Bisphosphonates
MOA
1. High affinity for Ca+2 & PO4 → internalize in osteoclast
by endocytosis → ↑ osteoclast apoptosis
2. Suppress IL6 → ↓ osteoclast differentation
3. Affect mevalonate pathway → ↑ apoptosis of
osteoclast
 PK
- Poorly absorbed, highly bound to Ca+2 & PO4 in bone

28. Uses
1. Osteoporosis → all types → Alendronate used OD or week
2. Paget’s disease (due to abnormal osteoclast function) →
Alendronate, Risedronate used .BPN efficacy > calcitonin.
Therefore BPN preferred
3. Hypercalcemia of malignancy (emergency) Pamidronate (IV),
Zoledronate (DOC, IV) plus Calcitonin IM x 2 days + IV drip &
furosemide
4. Osteolytic bone metastasis → ↓ bone pain
 ADR
- GI irritation- drug given half hour before meal with glass of
water in standing position-prevent esophagitis
- No concurrent use of NSAID
- Thrombophlebitis & flu like syndrome

29. Drugs Dose & Route Special features
Etidronate 5-7.5mg/kg daily, both oral & IV  It was the first bisphosphonate used clinically.
 Not in used nowadays due to its side effects
(osteomalacia).
Tiludronate 1mg/kg, intravenously  Used in animal only
 Not available in India.
Alendronate 5-10 mg once daily or 35-70 mg once weekly.  It is orally effective.
 Should be given empty stomach.
 Weekly treatment is preferred.
 The terminal elimination plasma half-life is 10.5
years.
Ibandronate 150mg once a month, orally.
3mg IV given over 15-30 seconds and repeat
every 3 months.
 Should be taken 60 minutes before meals.
Pamidronate 30-90 mg intravenously given over 2-4 hours.  Used only as IV infusion.
 Not given orally.
 Thrombophebitis may occur.
Risedronate 35 mg oral, weekly  It is orally effective.
 Should be given empty stomach with full glass of
water.
Zoledronate Method of administration
 Intravenous infusion of 4 mg to be
diluted in the 100 ml of saline/glucose
and given over 15 minute.
 Intravenous infusion of 4 mg yearly.
(osteoporosis in postmenopausal
women)
 Most potent bisphosphonate.
 Most preferred agent for hypercalcaemia.
 Least irritating effect to the vein.
 Flu like symptoms, nausea, vomiting may be seen.
 Renal toxicity may occur, which can be prevented by
liberal fluid intake.

32. Osteoporosis

33. case

35. Investigations
• X rays
• Vit- D Levels
• Ca & PO4 Levels
• Biopsy (Iliac crest)

36. How you can manage
• Vertebroplasty
• BPN
• NSAIDs
• Donesumab

37. • Osteoporosis is a systemic skeletal disorder
characterized by low bone mass and
microarchitectural deterioration of bone
tissue predisposing to an increased risk of
fracture.
• The clinical diagnosis combines evidence of
fragility fractures with measurement of bone
mineral density [BMD].

38. • BMD correlates with bone strength, skeletal load-
bearing capacity, and fracture risk.
• The widely used World Health Organization
[WHO] definitions compare patient BMD to
norms expressed as T-scores, the number of
standard deviations [SDs] from the mean BMD in
young white adult women.
• World Health Organization Definitions
Classification DXA T-score*
Normal Osteopenia
Osteoporosis
≥ -1.0 > -2.5 and < -1.0 ≤ -
2.5

39. Clinical Risk
Extremely High Risk High Risk Moderate Risk
• Prior osteoporotic
fracture
• Glucocorticosteroid
use ((prednisone ≥
7.5 mg/d or
equivalent for ≥ 6
months)
• Solid organ
transplant: (pre or
post, especially in
first 2-3 yrs
• Glucocorticosteroid
use:(prednisone ≥
5mg/ day or
equivalent, for ≥ 3
months)
• Woman age > 65 yrs
or men age > 70 yrs.
• Postmenopausal
woman or older man
with one or more of:
 Family history of
fracture hip, wrist, or
spine (first-degree
relative age ≥ 50 yrs)
 Currently smoking
 Rheumatoid arthritis
 Body Mass
Index[BMI]<20.
• Hypogonadism
• Late menarche (age > 15yrs)
• Early menopause (age<
45yrs)
• Premenopausal amenorrhea,
(e.g., anorexia nervosa,
exercise, or
hyperprolactinemia)
• Cushing’s syndrome
• Hyperparathyroidism
• Thyrotoxicosis
• Low gastric acid (e.g., atrophic
gastritis, proton pump
inhibitors, H2 –blockers)
• Impaired absorption
• Severe liver disease
• Chronic kidney disease
• Type 1 diabetes mellitus
• Thalassemia (major > minor)

41. DRUGS EFFECTS
Calcium (typically as
carbonate or citrate)
Total daily intake 1000-1500 mg
of elemental calcium
• Constipation is more common with calcium
carbonate
• Calcium citrate is more expensive, but
probably better absorbed in patients with low
stomach acidity (e.g., PPI use)
• Nephrolithiasis is not a contraindication
Vitamin D 800-1000iu/day • 0-30 min sun exposure to arms & face 2-
3x/week during summer months
• For high doses or calcitriol consider
specialist consultation

42. DRUGS EFFECTS
Bisphosphonates, oral
• Alendronate 70 mg po weekly
• Ibandronate 150 mg po monthly
• Risedronate 35 mg po weekly, 150
mg po monthly
Bisphosphonates, parenteral
• Ibandronate (3 mg IV Q 3 mo
• Zoledronic acid 5 mg IV yearly
 Take 30-60 min before 1st food of
day with 8 oz water; stand/sit
upright for 30-60 min
 Mild GI effects excess 0-5% cf.
placebo; severe GI effects are rare
 Reflux w/o esophagitis is relative
but not absolute contraindication
 Renally excreted, avoid if creatinine
clearance <30-35.
 Risk of osteonecrosis of jaw is less
than 1 in 100,000 for oral
bisphosphonates.
 For zoledronic acid – monitor for
increased creatinine and
hypocalcemia

43. DRUGS EFFECTS
Raloxifene 60mg od • Increased deep venous thrombosis
and pulmonary embolism risk.
• Hot flash incidence 3-6% greater than
placebo
• Not indicated for men or for
premenopausal women
Hormone therapy, Postmenopause
Estrogens
Estradiol 1 mg od
Estropipate 0.625 mg od
Conjugated estrogens 0.625 mg od
Transdermal estradiol (various) 0.05
mg/d 1-2x/wk
Combinations (dose ranges of
estrogen and progestin) 0.3/1.5 mg
daily to 0.625/2.5 mg daily
• The relative risks and benefits of
postmenopausal estrogen therapy
should be reviewed with patients
before starting treatment.
• Women with uterus in place will need
both estrogen and progestin therapy

44. Teriparatide 20 mcg SQ daily 
Denosumab 60 mg SQ q 6months • Administered in clinical settings
• Consider specialist consultations
• Denosumab is a monoclonal
antibody
• Small increase in skin infections
have been reported

45. CASE-II

46. Osteoporosis
• Case history: 68-year-old white woman
• Presents to accident and emergency
department with right wrist pain, swelling,
and displacement following a fall onto
outstretched hand on the stairs at home

47. History
• Past medical history – asthma since childhood (treated with
corticosteroids aged 50–55), gastric ulcer aged 45, menopause
age 59, left wrist fracture aged 67
• Family history – stroke in sister aged 65, hip fracture in mother
aged 78. Mother diagnosed with osteoporosis
• Social history – lives alone, 2 children, retired, smokes 5
cigarettes per day, occasional alcohol, takes no exercise, fully
mobile and able to complete all ADLs (activities of daily living)

48. Examination
• On examination – wrist displaced, swollen, no
open wound
• No loss of sensation or vascular compromise
• X-ray – Colles’ fracture of distal radius present
N.B. The most common osteoporotic fractures
are vertebrae, wrists, and hips. Lifetime risk of
fracture in white women is 20% for spine, 15%
for wrist, and 18% for hip. There is an
exponential increase in fracture over 50 years

49. Investigations and treatment for
presenting problem
• Colles’ fracture treated conservatively with
cast and analgesia
• DEXA scan arranged as postmenopausal
woman with history of previous fracture,
corticosteroid use, and family history of
osteoporosis – osteoporosis diagnosed in this
patient

50. Further issues for you to consider...
• How can further fractures be prevented?
• Bisphosphonates are the most commonly
used treatment, but how useful are they?
• Are there any non-pharmacological
treatments that would help?
• Which of these options are most appropriate
for this particular person?
• How strong is the evidence for these options?