This document provides an overview of osteoporosis including its definition, epidemiology, pathophysiology, causes, clinical features, diagnosis, and treatment. Some key points include: - Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. It is defined by the WHO as a bone density 2.5 standard deviations below the mean. - It is a major global health problem, particularly affecting post-menopausal women and the elderly. Lifetime risk of osteoporotic fractures is 30-50% in females and 15-30% in males. - Causes include failure to achieve peak bone mass, increased bone resorption, and inadequate bone formation

1. OSTEOPOROSIS
Presented by
Dr Rahul Roy
Dr Ram Mohan
Maj Guarav Datta
Moderator: Col J Muthukrishnan, SM
Professor, (Medicine & Endocrinologist)

2. OUTLINE
Definition
Epidemiology
Pathophysiology
Causes
Clinical features
Diagnosis
Treatment

3. OSTEOPOROSIS
Osteoporosis:
Skeletal disorder characterized by compromised
bone strength predisposing to an increased risk of
fracture.
Normal Bone Osteoporotic Bone

4. OSTEOPOROSIS
WHO definition:
Bone density that falls 2.5 standard deviations (SD)
below the mean for young healthy adults of the same
sex
Also referred to as a T-score of –2.5

5. T-score
A comparison of a patient's BMD to that of a healthy
young adult (20 years) of the same sex and ethnicity.
Normal T-score of -1.0 or higher
Z-score
A comparison of a patient's BMD to that of a
healthy adult of the same age, sex and ethnicity.
Used in premenopausal women, men under the
age of 50 and in children.

6. WHO, Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis.
T - Score
WHO Osteoporosis Guidelines

7. EPIDEMIOLOGY
Osteoporosis comes second to cardiovascular disease
as a global health problem Worldwide
Lifetime risk for osteoporotic fractures
 Females - 30-50%
 Males - 15-30%.
1.6 million hip fractures each year worldwide, the
incidence to increase to 6.3 million by 2050
Hip fractures 20 % mortality at one year
International Osteoporosis Foundation (IOF)

8. EPIDEMIOLOGY
India - One of the largest affected countries in the world.
1 out of 3 females
1 out of 8 males
High incidence of Hip # among men (men : women =1)
lower age of peak incidence (50 – 60 years) compared to
Western countries ( 70 – 80 years ).
International Osteoporosis Foundation

9. Background
The most common fractures in the elderly
osteoporotic patient include:
Hip Fractures
Femoral neck fractures
Intertrochanteric fractures
Subtrochanteric fractures
Ankle fractures
Proximal humerus fracture
Distal radius fractures
Vertebral compression fractures Image courtesy of International Osteoporosis Foundation

10. • Bone density is only one risk factor for fracture.
• Instead of treating the T score identified by DXA scans,
aim is to reduce an individual’s risk of future fracture.
• This change in emphasis has been enabled by the
development of fracture risk assessment tools (FRAX).
• The FRAX® tool has been developed by WHO to
evaluate fracture risk of patients.
ASSESSMENT OF FRACTURE RISK

11. The FRAX® tool

12. AGE T-Score
= -1.0
T-Score
= -2.5
50 6 % 11 %
60 8 % 16 %
70 12 % 23 %
80 13 % 26 %
RISK OF FRACTURES OVER 10 YEARS IN WOMEN
ABSOLUTE FRACTURE RISK IN 10 YEARS:
low: <10%
moderate: 10-20%
high: >20%

13. Peak bone mass
Skeletal mass increases from approximately 70 to 95 g at birth to 2400 to
3300 g in young individual
25% of PBM is acquired during the 2-year period across the adolescent
growth spurt
Factors affecting PBM
Hereditary factors
Ethnicity
Nutritional
Physical activity

16. Pathophysiology
There are three major pathogenetic reasons for low bone mass.
1. Failure to achieve optimal peak bone mass.
2. Increased bone resorption in osteoporotic patients.
3. Inadequate bone formation.

17. BoneMass
Age (years)
Attainment of Peak
Bone Mass
Consolidation Age-related Bone Loss
Men
Women
Menopause
0 10 20 30 40 50 60
Fracture
Threshold
Compston JE. Clin Endocrinol 1990; 33:653–682.
Pathophysiology

18. Pathophysiology
•In childhood bone formation exceeds resorption -continued skeletal
growth.
•Normal bone loss- 0.7 per cent per year.
•Menopause : 2-5 per cent per year, which may continue for up to 10
years
•Level of peak bone mass achieved at puberty is a major determinant

19. OSTEOPOROSIS - TYPES
•Primary (senile) osteoporosis
•Post menopausal osteoporosis
•Secondary osteoporosis

20. SECONDARY CAUSES OF OSTEOPOROSIS
Endocrine diseases
 Hypogonadism
 Hypothyroidism
 Hypoparathyroidism
 Cushing’s syndrome
Inflammatory diseases
 Inflammatory bowel diseases
 Rheumatoid Arthritis
 Ankylosing spondylitis

21. SECONDARYCAUSESOFOSTEOPOROSIS–DRUGS
•Aluminum (in antacids)
•Anticoagulants (heparin)
•Anticonvulsants
•Aromatase inhibitors
•Barbiturates
•Chemotherapeutic drugs
•Cyclosporine A & tacrolimus
•Depomedroxyprogesterone
•Glucocorticoids
•GNRH antagonists and agonists
•Lithium
•Methotrexate
•Proton pump inhibitors
•SSRI`s
•Tamoxifen (premenopausal use)
•Thiazolidinediones
•Thyroid hormones (in excess)
•Parenteral nutrition

22. Secondary causes of osteoporosis
GI diseases
 Malabsorption
 Chronic liver disease
Nutritional
 Calcium
 Vit D
 Magnesium
Miscellaneous causes
 Myeloma
 Immobilisation
 Homocysteinuria
 ESRD
 Gaucher’s disease
 Poor diet / low body weight

23. Risk factors Osteoporotic fractures
Non modifiable
• h/o fracture as an adult
• h/o fracture in 1o relative
• Females
• Age
• Caucasians
• Dementia
Potentially modifiable
• Smoking
• Low body weight(<58 kg)
• Estrogen deficiency
• Low Ca intake
• Alcoholism
• Impaired eye sight
• Falls
• Physical inactivity
• Poor health

24. Clinical features & Complications
•Pain in back
•Difficulty in bearing weight
•Kyphosis
•Loss of height
•Clinically diagnosed fracture
•Protuberant abdomen
•Depression
•Loss of productivity
•Loss of independence
•Death

25. CLINICAL DIAGNOSIS AND TREATMENT

26. Diagnosis
Radiographic measurement of bone density
Lab biomarkers
Bone biopsy with pathological assessment

27. Bone density
Single photon absorptiometry
Dual photon absorptiometry
Dual X ray absorptiometry
Qauntitative CT
Quantitative USG

28. Indications for Bone Density test
1.All postmenopausal women <65 yr who have one or more additional
risk factors for osteoporosis, besides menopause.
2.All women >65 yr regardless of additional risk factors.
3.Documenting reduced bone density in a patient with a vertebral
abnormality or osteopenia on a radiograph.
4.Estrogen-deficient women at risk for low bone density
5. Estrogen replacement therapy for prolonged periods to monitor
efficacy of a therapeutic intervention.
6.Diagnosing low bone mass in glucocorticoid-treated
individuals(Prednisolone at 7.5mg daily for 6m.)

30. Markers of bone formation
 Osteocalcin (OC)
 Bone specific alkaline phosphatase (bone ALP)
 Procollagen type 1 N-terminal propeptide (P1NP)
 Procollagen type 1 C-terminal propeptide (P1CP)

31. Bone resorption markers
 Pyridinoline (PYR)
 Deoxy pyridinoline (DPD)
 N-telopeptides of type 1 collagen (NTX)
 C-telopeptides of type 1 collagen (CTX)
 Pyridinolines are measured in urine
 Telopeptides can be measured in both serum and urine

32. WHOM TO TREAT
Women with a previous hip or vertebral fracture, fragility
fracture
T score of −2.5 or less at the hip, lumbar spine, or femoral neck,
T score between −1.0 and −2.5 and a 10-yr probability of hip
fracture >3% or of major osteoporotic fracture >20%
In presence of risk factors,
If FRAX score exceeds age-specific criteria
National Osteoporosis Guideline Group

33. BlackDM,RosenCJ.NEnglJMed2016 ;374:254-262.
Guidelines – Professional Organizations for Treatment of Osteoporosis.

34. Non Pharmacological measures
•Regular weight-bearing & muscle strengthening exercise,
•Fall-prevention strategies,
•Avoid smoking and excess alcohol intake
•Diet rich in calcium & Vit D supplementation

35. Pharmacological measures
1. Ca-rich diet,↑ Ca Supplements
2. Vit-D (monitor serum+urine Ca).
3. Estrogens/Androgens
4. Biphosphonates ( inhibit osteoclast mediated bone resorption )
5. Calcitonin
6. PTH-Teriparatide/(Forteo )=intermittent low doses

36. Drugs Approved by the FDA for Treatment and Prevention of Osteoporosis.
Black DM, Rosen CJ. N Engl J Med 2016;374:254-262

37. Osteoporosis Prevention and Treatment
Age
Hormonal Replacement
Bisphosphonates
Strontium
SERM
20 40 60 80
Vitamin D
PTH
Life Style
Treatment
choice

38. Ca supplements
CALCIUM PREPARATION
Ca Citrate
Ca Lactate
Ca Gluconoate
Ca Carbonate
Ca Carbonate + 5 ug Vit D2
(Oscal 250)
Ca Carbonate (Turns 500)
ELEMENTAL CALCIUM
60 mg/300 mg
80 mg/600 mg
40 mg/500 mg
400 mg/g
250 mg/tablet
500 mg/tablet

39. Calcium and Vitamin D
•Inadequate calcium intake in adults older than 70 years of age is
associated with increased bone loss and increased risk of fracture
•Observational studies suggest that bone loss and fracture risk increase
when calcium intake is below 700 to 800 mg per day.
•Combining Vitamin D and calcium supplementation has been
shown to increase bone mineral density and reduce the risk of
fracture.
Age Calcium/day (mg)
0-6 months 210
6 months-1 yr 270
1-3 500
4-8 800
9-18 1300
19-50 1000
51-70 1200
Vitamin-D requirement

40. Selective Estrogen Receptor Modulator
(SERM)(Evista®) Raloxifene, RALOXIFENE
Reduces vertebral (not non-vertebral) fracture risk
Reduces development of new breast Ca.
No increased risk of CVD (reduces CV events!)
Increased risk of thromboembolism
May worsen flushes
Well tolerated, easy dosing

41. BISPHOSPHONATES
•Etidronate, risedronate (Actonel®), alendronate(Fosamax®),
ibandronate (Boniva®), zoledronate
•Interfere with action of osteoclasts &decrease bone resorption,
•Alendronate and risedronate firstline option in postmenopausal
osteoporosis
•IV Biphosphonates – Zolendrenate , Ibandronate
•Strict dosing instructions
•Contraindicated in patients with GFR<35 ml/min, , vitamin D
depletion, osteomalacia or Hypocalcemia

42. Clinical use of strontium ranelate
(Protelos)
In women with postmenopausal osteoporosis:
 Alternative to bisphosphonates, particularly in the elderly
if potential for upper gastrointestinal complications
 Intolerance or inadequate response with other osteoporosis
therapies
 Beware of rash (DRESS) and VTE (RR 1.4)

43. (Miacalcin®) Calcitonin
For paget’s disease, hypercalcemia, osteoporosis in women > 5
years post menopause
Nasal Spray-200 IU/L
Mechanism-small increments in bone mass and small
reduction in new vertebral fractures
Not useful in non vertebral fractures
May have an analgesic effect on bone pain

44. PTH- 1-34h Teriparatide
•PTH- although causes bone loss in chronic elevated condition ,
has an anabolic effect on bone.
•Maintainence of trabecular bone mass
•20 ug PTH sc daily- 65% ↓ in vertebral fractures and 45%↓ in
nonvertebral fractures
•Single daily dose for maximum of 2 years
•For treatment naïve patients- montherapy f/b bisphosphonate
•S/E- muscle pain, headache, dizziness and nausea

45. DENOSUMAB
Monoclonal Ab to RANKL which drives osteoclasts
Subcut every 6/12! 60mg
Dramatic and quick effect
Fracture reduction similar to Zoledronate
Cost similar to risedronate (in 2010)
NICE appraised

46. DenosumabBindsRANKLigandandInhibitsOsteoclast
Formation,Function,andSurvival
RANKL
RANK
OPG
Denosumab
Bone Formation Bone Resorption Inhibited
Osteoclast Formation, Function,
and Survival Inhibited
CFU-GM Prefusion
Osteoclast
Osteoblasts
Hormones
Growth Factors
Cytokines
Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342.

47. RECENT ADVANCES - DRUGS

48. • Odanacatib— cathepsin K inhibitors .
• In phase 1 studies, odanacatib at an oral dose of 50 - 100 mg once a week
reduced serum levels of the bone resorption marker C-terminal
telopeptide of type I collagen (CTX) by 62%.
• Daily administration of odanacatib (10 mg) reduced serum CTX by 81%.64
• After 24 months, odanacatib (50 g)increased BMD of the lumbar spine and
total hip by 5.7% and 4.1% compared to placebo,
• Adverse reactions :scleroderma-like cutaneous lesions were not observed.
• Currently, a phase 3 study is being conducted with over 16,000
postmenopausal women to assess the antifracture efficacy of odanacatib.
Odanacatib

50. Saracatinib : Src kinase inhibitor
Dose-dependent decrease in serum C-terminal telopeptide of
type I collagen levels and urinary N-terminal telopeptide of
type I collagen.
Bone formation markers were similar to placebo.
Adverse reactions: papular rash and loose stools
SARACATINIB (AZD0530)

51. • Calcilytic agents (MK-5442)—Calcilytics represent a new
class of bone-forming agents.
• Act as antagonists of the CaSR and mimic hypocalcaemia,
thus evoking a short pulse of PTH secretion.
• Calcilytics are administered orally and obviate the need for
injections as opposed to PTH therapy.
• Narrow therapeutic index.
• These compounds led to sustained PTH secretion and findings
that were reminiscent of primary hyperparathyroidism, a
catabolic bone disease.
Anabolic therapies

52. • Wnt-dependent nuclear accumulation of β-catenin is a
major trigger of osteoblastic differentiation and bone
formation.
• The endogenous inhibitors of Wnt signalling, sclerostin and
Dkk-1 present potential therapeutic targets to enhance
osteoblastic bone formation and are under clinical
investigation.
• Sclerostin antibody
• Dickkopf-1 antibody (BHQ-880)
Inhibitors of Wnt antagonists