Osteoporosis and its complication

1. OSTEOPOROSIS
Moderator- Dr. S Ranabir, Associate Professor
Presenter- Dr. Supriya Jamatia

2. INTRODUCTION
• Osteoporosis defined as a reduction in the strength of bone
that lead to an increased risk of fractures
• WHO- Bone density that falls 2.5 standard deviation (SD)
below the mean for young healthy adults of the same sex
also referred to as a T score of ≤ -2.5

3. BONE STRUCTURE
• Types of bone
 Cortical bone - 80% of total bone
- Dense type of bone that surrounds the
cancellous bone to form outer durable layer.
 Cancellous (trabecular) bone
- 20% of total bone
- Interconnected structure of lattice work
porous, spongy inner structure of the bone.

5.  Osteoblast, Osteocytes and Osteoclasts
 Osteoblast and Osteocytes are derived from mesenchymal
stem cells
 During remodelling Osteoblast lay down layers of bone that
add strength to the matrix
Types of bone cells

6.  Some of the osteoblast are buried in the matrix to become
osteocytes
 Osteoclasts originate from hematopoietic stem cells
 Osteoclasts are the cells that remove old bone by
dissolving the mineral and breaking down the matrix in a
process called bone resorption

7. EPIDEMIOLOGY
• Osteoporosis occur more frequently with increasing age as
bone tissue is lost progressively
• More in women as loss of ovarian function at menopause
precipitates rapid bone loss and lower peak bone mass
• In India around 36 million people have osteoporosis
• 1 out of 8 males and 1 out of 3 females in India suffer from
osteoporosis

8. • Around 80% of people with osteoporosis are women
• While the peak incidence of osteoporosis occur at about
70-80 years of age, in India it may afflict at age of 50-60
years of age
• Osteoporosis is responsible for one and half million
fracture / year
• World wide over 200 million people have osteoporosis

9. PATHOPHYSIOLOGY
• Bone remodelling has two primary functions
 To repair micro damage within the skeleton to maintain skeletal
strength and relative youth of the skeleton
 To supply calcium from the skeleton to maintain serum calcium
• After 30-45 years of age, bone resorption exceeds formation
• Remodelling may be activated by micro damage to bone as a
result of excessive or accumulated stress

10. • Osteoblast synthesize and secrete the organic matrix and
regulate new bone formation
• Osteoclasts mainly carried out resorption of bone
• Excessive bone loss can be due to an increase in osteoclastic
activity or decrease in osteoblastic activity
• Nutrition and lifestyle play important role in growth
although genetic factors primarily determine peak skeletal
mass and density

11. Pathway regulating development of
osteoblast and osteoclast

12. PROCESS OF BONE REMODELLING

13. Hormonal control of bone remodelling

14. EVENT STIMULATORY FACTOR INHIBITING FACTOR
BONE RESORPTION
PARATHYROID
HORMONE
CORTISOL
THYROXINE
PROSTAGLANDINS
INTERLEUKIN 1
INTERLEUKIN 6
OESTROGEN
ANDROGEN
CALCITONIN
TRANSFORMING GROWTH
FACTOR B
INTERFERON
NITRIC OXIDE
FACTORS REGULATING BONE
REMODELLING

15. EVENT STIMULATORY EFFECT INHIBITORY EFFECT
BONE FORMATION
GROWTH HORMONE
INSULIN LIKE GROWTH FACTOR
TESTOSTERONE
OESTROGEN
TGF B
SKELETAL GROWTH FACTOR
BONE DERIVED GROWTH
FACTOR
CALCITONIN
CORTISOL

16. RISK FACTORS
 Previous fracture after age 30 years
 Family history of hip fracture
 Cigarette smoking
 Weight< 127 lb
 Low bone mineral density
Primary

17.  Low calcium intake
 Eating disorder
 Low testosterone level
 Pre menopausal estrogen deficiency
 Excessive alcohol intake
 Physical inactivity
 Impaired vision
 Neurologic disorder
 Lack of sunlight exposure
Secondary
(modifiable)
 White race, advanced age
 Poor health
 Dementia
Secondary
(non-modifiable)

18. Medical disorder and medication associated
with osteoporosis
• Primary osteoporosis
Juvenile osteoporosis
Post menopausal osteoporosis
• Endocrine abnormalities
Glucocorticoid excess
Thyroid hormone excess
Hypogonadism
Hyperparathyroidism
• Immobilization

19. • Process affecting bone marrow
 Multiple myeloma, leukemia, gaucher disease
• Gastrointestinal disorder
 Celiac disease, gastrectomy
• Renal insufficiency
• Chronic respiratory disease
• Connective tissue disease
 Osteogenesis imperfecta
• Rheumatologic disorder

20. • Medications
Corticosteroid
Anticonvulsants
Heparin
Methotrexate
Cyclophosphamide, GnRH agonists
Lithium
Cyclosporine
Aluminum
Aromatase inhibitors

21. CLINICAL FEATURES
• Mostly – asymptomatic
• Acute back pain – due to vertebral fracture
• Gradual onset of height loss and kyphosis with chronic pain
• The pain of VCF can radiate to the anterior chest or
abdominal wall

22. • Lumbar fractures can be associated with abdominal
symptoms like distension, early satiety and constipation
• Peripheral osteoporotic fractures- local pain, tenderness
and deformity
• Hip fracture, the affected leg is shortened and
externally rotated

23. INVESTIGATIONS
 Clinical determination are made of the lumbar spine and hip
 T score below -2.5 in the lumbar spine, femoral neck or total
hip has been defined as osteoporosis
 It determine mass of bone mineral in the path of the beam
divided by the cross sectional area of the beam expressed as
g/cm2
Dual Energy X Ray Absorptiometry (DXA)

24.  DXA can be used to obtain lateral images of thoracic and
lumbar spine, a technique called vertebral fracture
assessment(VFA)
 If only one skeletal site can be measured it is best to assess
the spine in individuals < 60 years and hip in > 60 years

25. Indication for BMD testing
• Women aged ≥65 yrs and men aged ≥70; regardless of
clinical risk factors for fracture
• Younger postmenopausal women, women in the
menopausal transition, and men aged from 50 to 69
with clinical risk factors for fracture
• Adults who have fracture at or after age 50

26. • Adults with a condition (e.g., rheumatoid arthritis) or
taking a medication ( e.g. , glucocorticoids at a daily
dose > 5mg prednisone or equivalent for > 3 months)
associated with low bone mass or bone loss

27. INDICATIONS FOR VERTEBRAL IMAGING
• All women aged ≥70 yrs and all men aged ≥80 yrs if BMD
T-score at the spine, total hip, or femoral neck is < 1.0
• Women aged from 65 to 69 and men aged from 70 to 79 if
BMD T-score at the spine, total hip, or femoral neck is <1.5

28. • Postmenopausal women and men aged ≥50 with
specific risk factors:
– Low-trauma fracture during adulthood (aged≥50)
– Historical height loss of ≥1.5 in.(4cm)
– Prospective height loss of ≥0.8 in. (2cm)
– Recent or ongoing long-term glucocorticoid treatment

29. • BONE BIOPSY
 Tetracycline labelling of the skeleton determine rate of
remodelling and evaluation of other metabolic bone diseases.
 Not used for diagnosis
• BIOCHEMICAL MARKERS
 It provide an earlier estimate of patient response than bone
densitometry

30. Markers of Bone turnover
Bone Formation Bone Resorption
1. Bone specific alkaline
phosphatase (BAP)
2. Osteocalcin
3. C-terminal propeptide of type І
procollagen
4. N-terminal propeptide of type І
procollagen
1.C-terminal cross linked telopeptide of
type І collagen
2. N-terminal cross linked telopeptide of
type І collagen
3. Hydroxylysine-glycosides
4. Hydroxyproline
5. Pyridinoline
6. Deoxypyridinoline

31. Indication for Biochemical markers
• Predict risk of fracture independently of bone density
• Predict extent of fracture risk reduction when repeated
after 3-6 months of treatment
• Predict magnitude of BMD increases with therapies
• Predict rapidity of bone loss
• Help determine adequacy of patient compliance to
therapy
• Help determine duration of ‘drug holiday’

32. • ROUTINE TEST
 Complete blood count
 Serum and 24 hour urine calcium
 Renal and hepatic function test
 25(OH)D level
 TSH
 Urinary free cortisol or fasting serum cortisol
 X ray

33. Risk assessment tool (FRAX)

34.  FRAX incorporates femoral neck BMD to assess 10 year
fracture risk
 cost effective to treat a patient if the 10 year major
fracture risk ( hip, spine, proximal humerus, tibia) from
FRAX > 20% and 10 year risk of hip fracture > 3%
 does not include any assessment of risk of fall and
secondary causes are excluded
 does not include any term for multiple fractures or recent
versus remote fracture

35. TREATMENT
• When to start treatment
 When there is hip or vertebral fracture (clinical or
asymptomatic)
 When BMD is > 2.5 SD below the mean value for young adults
(T score ≤ -2.5) in either spine, total hip or femoral neck
 Post menopausal women and men >50 years with fracture risk
factors even if BMD is not in the osteoporosis range

36. Management of underlying disease
• Risk factor reduction
• Nutritional recommendations
- Calcium: 1200mg/day ,doses of supplements should be <600
mg per single dose
- Vit D: (serum 25(OH) D level should >30 ng/ml)
- recommends daily intake
- Age < 50yrs  200 IU
- 50-70 yrs  400 IU
- >70 yrs  600 IU
• Exercise

37. Algorithm for management of postmenopausal
osteoporosis
Low- moderate risk High-very high risk
Low risk Moderate risk
Reasses
fracture risk
in 2-4 yrs
Bisphosphonates
Reasses#risk in 3-5yrs
(5yrs for oral 3 yrs for iv)
Denosumab
Reasses#risk in 5-10yrs
Teriparatide or
Abaloparatide
2yrs
Calcium
VitD
as
adjunct
therapy
OR
All postmenopausal women
1) Lifestyle and nutritional optimization for bone health especially calcium and Vit D.
2) Determine the 10 yr fracture risk

38. Low-Mod risk
1.consider drug
holiday
2.Reasses#risk
every 2-4 yrs
3. If bone loss or
pt become high
risk , consider
restarting therapy
High risk
continue
therapy or
switch
therapy
Intolerant to
or
inapproprite
for above
therapies
Low-mod risk
consider giving
bisphonates and then
stopping for drug
holiday,
reasses#risk every 1-3
yrs,
if bone loss#occurs or
pt become high risk,
consider restarting
therapy
High risk
continue
therapy or
switch
therapy
Bisphosphonates
Reasses#risk in 3-5yrs
(5yrs for oral 3 yrs for iv)
Denosumab
Reasses#risk in 5-10yrs
Teriparatide or
Abaloparatide
2yrs
Algorithm - continued

39. Intolerant to or
inapproprite for
above therapies
Age <60 or
<10 yrs past menopause
low VTE risk
No vasomotor symptoms,
high breast cancer risk
Age > 60
yrs
SERM(raloxifene
,bazedxifene)
With vasomotor
symptoms
HT (no uterus,Estrogen;
with uterus Estrogen+Progersteron) or
Tibolone
Consider (in order):
1.SERM
2.HT/Tibolone
3.Calcitonin
4.Calcium+VitD
Algorithm - continued

41. Pharmacologic treatment
Antiresorptive Agents
1. Estrogen, Progesteron, Tibolone -
 reduce bone turn over, prevent bone loss, and induce small
increase in bone mass (50% )
 Act on ERs especially α, inhibit osteoclast directly and
stimulate osteobast to produce paracrine factor.
 Increased risk of fatal and non fatal MI, STROKE, venous
thromboembolism, breast cancer

42. 1. Raloxifene, Bazedoxifene:
 Estrogen antagonist on breast and estrogen agonist on bone,
lipids, clotting factors and endometrium.
 Use in pt with low risk of deep vein thrombosis (DVT) and for
whom bisphosphonates or denosumab are not appropriate, or
with a high risk of breast cancer.
 Raloxifene 60mg once daily.
SELECTIVE ESTROGEN RECEPTOR MODULATORS

43. • Mechanism of action
 Impair osteoclast function and number, in part by inducing
apoptosis
• Side effects
 Osteonecrosis of the jaw, subtrochanteric or atypical fracture
femur
BISPHOSPHONATES
Reduces the incidence of vertebral, hip and
other major fracture by 68%, 40% and 20%.

44. BISPHOSPHONATES
Alendronate Risedronate Ibadronate Zoledronic acid
DOSE 5-10 mg/day
70mg/weeky
5mg/day,
35mg/wk,
150mg/month
150mg/month ,
3mg/3month
5 mg annually
ROUTE Oral oral Oral, IV
respectively
IV over 15 min

45.  Indicated in post menopausal osteoporosis who cannot tolerate
raloxifene, bisphosphonates, estrogen, denosumab, tibolone,
abaloparatide, or teriparatide or for whom these therapies are
not considered appropriate.
 Side effects - nausea, flushing and local irritation, long term use
increase risk of prostate and liver cancer and other malignancy
CALCITONIN
(Dose- 100 IU sc/im daily/weekly, 200 IU nasal spray)
Suppresses osteoclast
activity by Direct action on
osteoclast calcitonin receptor

46.  Stimulate calcium uptake in bone while inhibit bone
resorption
 Orally administered. Approved by European regulatory
agencies not by FDA
 Increased cardiovascular events
Strontium Ranelate

47.  Human monoclonal antibody to the RANKL
 Post menopausal osteoporosis with high risk of fracture, Men with
prostrate cancer on GnRH therapy, Women with breast cancer on
aromatase inhibitor
 Side effects- hypocalcemia, ONJ, AFF, cellulitis, dermatitis, rashes
 Reduces vertebral, hip and non vertebral fracture by 70, 40 & 20%
DENOSUMAB
( Dose – 60 mg sc every 6 month)
It bind to RANKL &
inhibit its ability to initiate
formation of mature osteoclast

48. ODANACATIB
 Cathepsin K inhibitor (an enzyme released from osteoclasts
that degrades collagen I in the bone matrix)
 A phase III study (LOFT): 50 mg/day reduces vertebral, hip,
non vertebral fracture by 54%, 47% & 23%
 Morphea like skin lesion and atypical femoral fracture were
observed more often in the Odanacatib group

49. 1. Teriparatide and Abaloparatide (PTH and PTH-Related
Protein Analogs)
 Approved for the treatment of osteoporosis in both men
and women with very high risk and with multiple vertibral
fracture
 Dose- 20-40 mcg/day sc injection
ANABOLIC AGENTS
PTH stimulates wnt, IGF-I and
collagen production and increase osteoblast
number by replication and inhibiting apoptosis

50. Effect of parathyroid hormone treatment
 Side effects- leg cramps, muscle pain, weakness, dizziness, headache and nausea
 Reduces vertebral and non vertebral fractures by 65 and 45%

51.  Monoclonal antibody
 Inhibit Wnt signalling antagonist sclerostin
 A phase II clinical trial reported that a monthly treatment with
romosozumab for 12 months increased lumbar spine bone mass
by 12%, femoral neck by 4% and total hip by 4%
 Phase III studies are ongoing to determine whether it can reduce
incident of hip fracture in post menopausal women with
osteoporosis
ROMOSOZUMAB

52.  Men with osteoporosis, hypogonadism and symptoms of low
libido
 Testosterone cypionate or enanthate(50-400mg im every 2-
4weeks)
 Transdermal testosterone patch(2.5-6mg/day)
 Bone mass increases with testosterone replacement when
level were initially low at the time of initiation
TESTOSTERONE

53.  Depending on the location and severity of the fractures
procedures may include open reduction and internal
fixation, hemiarthroplasty and total arthroplasty
 Long bone fractures often require either external and
internal fixation
 Vertebral, rib and pelvic fracture usually managed with
supportive care requiring no specific orthopaedic treatment
Treatment of patients with osteoporotic fracture

54.  BMD is considered as a monitoring tool, should be repeated at
intervals> 2 years
 Changes must exceed 4% in the spine and 6% in the hip to be
considered significant in any individual
 Biochemical marker of bone turnover may prove useful for
treatment monitoring
 Determination should be made before therapy is started and
repeated > 4 month after therapy
 Change in bone turnover markers must be 30-40% lower than
the baseline to be significant
Treatment monitoring

55.  Reducing risk factors for bone loss(hypogonadism, decreased
body fat, cigarette smoking, inactivity, alcohol intake)
 Patient should be advised to consume adequate vitamin D and
calcium
 Patient should be advised to participate in a regular weight
bearing exercise
 Avoid caffeine
Preventive measures

56. THANK YOU

57. REFERENCE
1. Harrison’s internal medicine, 20th edition
2. 2016 William’s Endocrinology, 13th edition
3. Pharmacological management of Osteoporosis in
postmenopausal women: An Endocrine society clinical practice
guideline, first online published on 25th march 2019