This document discusses osteoporosis and related bone diseases. It defines osteoporosis as a metabolic bone disease characterized by low bone density and increased bone fragility. Common fracture sites are the forearm, vertebrae, humerus and hip. Hip fractures are the most serious with a 12% immediate mortality rate. The document outlines risk factors, pathophysiology, clinical features, investigations and management strategies for osteoporosis as well as related diseases including vitamin D deficiency, osteomalacia, rickets, and hereditary disorders.

1. OSTEOPOROSIS

2. Osteoporosis is a metabolic skeletal disease characterised by low bone density and micro
architectural deterioration of bone tissue which results in increased bone fragility and susceptibility to fracture in
response to minor trauma.

3.  It is the most common bone disease.
 Fractures in patients with osteoporosis can affect any bone but common sites are the forearm (Colles’
fracture), spine (vertebral fractures), humerus and hip.
 Of these, hip fractures are the most serious and have an immediate mortality of about 12%.

4. Fractures
associated with
osteoporosis
A. Wrist
B. Vertebrae
C. Humerus
D. hip

5. Pathophysiology:
 The defining feature of osteoporosis is reduced bone density, which causes micro-architectural deterioration of bone tissue
and leads to an increased risk of fracture, in response to minor trauma.
 The risk of fracture increases markedly with age in both genders.
 Bone mass increases during growth to reach a peak between the ages of 20 and about 45 years, but falls thereafter in both
genders with an accelerated phase of bone loss after the menopause in women due to oestrogen deficiency.
 The loss of bone with ageing is caused by an imbalance in the bone remodelling cycle, whereby the amount of new bone
formed by osteoblasts cannot keep pace with the amount that is removed by osteoclasts.

7.  Idiopathic osteoporosis:
The term used to describe the occurrence of osteoporosis in patients with
no specific underlying cause.
 Secondary osteoporosis:
Osteoporosis can occur in association with a variety of diseases and drug
treatments.
 Glucocorticoid-induced osteoporosis:
Glucocorticoids mainly cause osteoporosis by inhibiting bone formation and
causing apoptosis of osteoblasts and osteocytes.
 Pregnancy associated osteoporosis:
Rare form of osteoporosis that typically presents with
back pain and multiple vertebral fractures during the second
or third trimester.

8. Clinical Features:
 Fragility fractures : a fracture that occurs as the result of a fall from standing height or less.
 The clinical signs of fracture are pain, local tenderness and deformity.
 In hip fracture, the patient is unable to weight-bear and has a shortened and externally rotated limb on the affected
side.

9.  The presentation of vertebral fractures is variable.
 Some patients present with acute severe back pain. This may radiate to the anterior chest or abdominal wall
and be mistaken for a myocardial infarction, aortic dissection or intra-abdominal pathology.
 In others the presentation is with height loss and kyphosis in the absence of pain or with chronic back pain.

10.  Sometimes the presentation of osteoporosis is with radiological osteopenia or as a
vertebral deformity on an X-ray.

11. Investigations:
 The most important investigation is Dual X-Ray Absorptiometry (DXA) at the lumbar spine and hip.
 Indications for dual X-ray absorptiometry (DXA):
 Low-trauma fracture, age > 50 years
 Clinical risk factors and 10-year fracture risk > 10%
 Glucocorticoid therapy (> 7.5 mg prednisolone daily for > 3 months)
 Assessment of response of osteoporosis to treatment
 Assessment of progression of osteopenia to osteoporosis
 Age < 50 years and very strong risk factors for osteoporosis

14. Management:
1. Non-pharmacological interventions:
 smoking cessation
 reduce alcohol intake
 adequate dietary calcium intake
 exercise
 Those with recurrent falls or unsteadiness on a ‘get up and go’ test should be referred to a multidisciplinary falls prevention team.
 Hip protectors can reduce the risk of hip fracture in selected patients but adherence is often poor.

15. 2. Pharmacological interventions:
a) Bisphosphonates:
First-line treatment for osteoporosis.
They target bone surfaces and are ingested by osteoclasts during the process of bone
resorption.
The bisphosphonate is released within the osteoclasts and impairs bone resorption.
This in turn causes an increase in bone density but this is principally due to increased
mineralisation of bone, rather than an increase in bone mass.

16.  Oral bisphosphonates are typically given for a period of 5 years, after which a repeat
DXA is taken if possible.
 If patients have remained free of fractures after 5 years and if BMD levels have
increased and no longer remain in the osteoporotic range, it is usual to instigate a 5-
year spell off therapy.
 Treatment may be continued for up to 10 years in patients whose BMD levels remain
in the osteoporotic range after 5 years.

18.  A change in treatment should be considered in patients who have lost BMD despite
oral bisphosphonates.
 Most commonly, this will be a switch to parenteral zoledronic acid but teriparatide
(TPTD) can also be considered in those with severe spinal osteoporosis.
 With intravenous zoledronic acid, 3 years of therapy is equivalent to 6 years in terms
of fracture risk reduction.

19. b) Denosumab:
 monoclonal antibody that inhibits bone resorption by neutralising the effects of RANKL.
 administered by subcutaneous injection of 60 mg every 6 months in the treatment of osteoporosis.
 has similar efficacy to zoledronic acid.
 One potential adverse effect is hypocalcaemia but this can be mitigated by calcium and vitamin D supplements.

20. c) Calcium and vitamin D:
 Combined calcium and vitamin D supplements are widely used as an adjunct to other treatments.
 A typical daily dosage is 1000 mg calcium and 800 IU vitamin D.
d) Teriparatide Teriparatide (TPTD):
 works by stimulating new bone formation.
 It is given by a self-administered subcutaneous injection in a dose of 20 μg daily for 2 years.
 At the end of this period, bisphosphonate therapy or another inhibitor of bone resorption should be administered to maintain the
increase in BMD.

21. e) Abaloparatide:
 It works in a similar way to TPTD to stimulate bone formation.
 It is given as a self-administered injection of 80 μg daily for 18 months.
f) Hormone replacement therapy:
 Cyclical HRT with oestrogen and progestogen prevents post-menopausal bone loss.
g) Raloxifene:
 selective oestrogen receptor modulator (SERM)
 acts as a partial agonist at oestrogen receptors in bone

22. h) Tibolone : partial agonist activity at oestrogen, progestogen and androgen receptors.
i) Other drugs:
 Romosozumab
 Calcitriol
j) Orthopaedic surgery with internal fixation is frequently required to reduce and stabilise osteoporotic fractures.

24. Vitamin D deficiency

25.  Vitamin D deficiency is defined to exist when serum 25(OH)D concentrations are below 25 nmol/L (10 ng/mL).
 People with vitamin D levels in the range 25–50 nmol/L (10–20 ng/mL) are classified as having vitamin D insufficiency,
whereas those with 25(OH)D levels above 50 nmol/L (20 ng/mL) are classified as having normal vitamin D status.

27. Pathogenesis:

28. Clinical Features:
 Vitamin D deficiency does not cause symptoms.
 the diagnosis is made as the result of biochemical testing.
 Low circulating concentrations of vitamin D have been associated with a wide range of diseases, including most types of
cancer, diabetes, multiple sclerosis and chronic inflammatory diseases.
 Prolonged and severe Vitamin D deficiency can cause Osteomalacia and Rickets.

29. Investigations:
 serum 25(OH)D
 PTH
 serum calcium
 Serum phosphate
 ALP

30. Management:
 Vitamin D supplements
 cholecalciferol in a dose of 800 IU daily
 In patients who are receiving intravenous bisphosphonates and denosumab for osteoporosis, vitamin D deficiency should
be corrected by supplementation to reduce the risk of hypocalcaemia.
 In this case, it is customary to give higher doses of vitamin D, such as 20 000–25 000 IU once a week for 4 weeks or to give
lower doses over a more prolonged period.

31. Osteomalacia
and
Rickets

32.  Osteomalacia and rickets are characterized by defective mineralization of bone.
 The most common cause is vitamin D deficiency, but both conditions can also occur as the result of inherited defects in
renal phosphate excretion, and inherited defects in the vitamin D receptor and in the pathways responsible for vitamin D
activation.
 The term osteomalacia refers to the syndrome when it occurs in adults and rickets is the equivalent syndrome in
children.

34. Pathogenesis:
 occur as the result of chronic secondary hyperparathyroidism, which invariably accompanies severe and long-
standing vitamin D deficiency.
 The sustained elevation in PTH levels maintains normal levels of serum calcium by increasing bone resorption, which
eventually causes progressive demineralisation of the skeleton.

35.  Phosphate that is released during the process of bone resorption is lost through increased renal excretion, resulting in
hypophosphataemia.
 The raised levels of PTH stimulate osteoblast activity and cause new bone formation but the matrix is not mineralized
properly because of deficiency of calcium and phosphate.
 The under-mineralised bone is soft, mechanically weak and subject to fractures, particularly stress fractures.

36. Clinical Features:
A. Rickets:
 delayed development in children
 muscle hypotonia
 craniotabes (small unossified areas in membranous bones of the skull that yield to finger pressure with a cracking feeling)
 bossing of the frontal and parietal bones and delayed anterior fontanelle closure
 enlargement of epiphyses at the lower end of the radius
 swelling of the rib costochondral junctions (‘rickety rosary’)

37. B. Osteomalacia:
 fractures and low BMD, mimicking osteoporosis
 bone pain and general malaise
 Proximal muscle weakness
 patient may walk with a waddling gait and struggle to climb stairs or stand up from a chair
 bone and muscle tenderness on pressure
 focal bone pain due to fissure fractures of the ribs and pelvis

38. Investigations:
 serum 25(OH)D – undetectable usually
 PTH - markedly elevated
 Calcium - usually normal, unless the disease is advanced.
 phosphate – tends to be low
 ALP - raised
 X-rays often show osteopenia or vertebral crush fractures and, with more advanced disease, focal radiolucent areas
(pseudofractures or Looser’s zones) may be seen in ribs, pelvis and long bones

39.  In children, there is thickening and widening of the epiphyseal plate.
 A radionuclide bone scan may show multiple hot spots in the ribs and pelvis at the site of fractures and the
appearance may be mistaken for metastases.
 Where there is doubt, the diagnosis can be confirmed by bone biopsy, which shows the pathognomonic features
of increased thickness and extent of osteoid seams .

40. Management:
 Osteomalacia and rickets respond promptly to treatment with vitamin D.
 Treatment with between 10000 and 25000 IU daily for 2–4 weeks is associated with rapid clinical improvement, an
elevation in serum 25(OH)D and a reduction in PTH.
 Serum ALP levels sometimes rise initially as mineralisation of bone increases but eventually fall to within the reference
range as the bone disease heals.
 Subsequently, the dose of vitamin D can usually be reduced to a maintenance level of 800–1600 IU daily (10–20 μg),
except in patients with malabsorption, who may require higher doses.

41. Vitamin D resistant rickets:
 genetically determined condition that presents in childhood with rickets that is resistant to therapy with vitamin D in
standard dosages.
 Type I vitamin D-resistant rickets (VDRR) is caused by inactivating mutations in the 25-hydroxyvitamin D 1α-hydroxylase
(CYP27B1) enzyme, which converts 25(OH)D to the active metabolite 1,25(OH)2D3.
 Type II VDRR is caused by inactivating mutations in the vitamin D receptor, which impair its ability to activate gene
transcription.
 Both are recessive disorders and consanguinity is common.

42.  The diagnosis is usually first suspected when the patient fails to respond to vitamin D supplementation.
 The biochemical features of type I VDRR are similar to those of ordinary vitamin D deficiency, except that levels of
25(OH)D are normal but 1,25(OH)2D is low.
 In type II VDRR, 25(OH)D is normal but PTH and 1,25(OH)2D3 values are raised.
 Type I VDRR responds fully to treatment with the active vitamin D metabolites 1α-hydroxyvitamin D (1–2 μg daily, orally)
or 1,25-dihydroxyvitamin D (0.25–1.5 μg daily, orally).
 Type II VDRR sometimes responds partially to very high doses of active vitamin D metabolites.

43. Hereditary hypophosphataemic rickets:
 caused by inherited defects in renal tubular phosphate reabsorption.
 The most common is X-linked hypophosphataemic rickets (XLH).
 associated with raised circulating concentrations of the phosphate-regulating hormone fibroblast growth factor 23
(FGF23).
 Production of FGF23 by osteocytes is under tonic inhibition by DMP1 and PHEX.
 In XLH, the inhibitory effect on FGF23 production is lost due to mutations in PHEX.
 a similar situation occurs in autosomal recessive hypophosphataemic rickets (ARHR1) due to loss-of-function mutations in
DMP1.

44.  the elevation in FGF23 results in osteomalacia and rickets by causing phosphaturia by up-regulation of sodium-dependent
phosphate transporters in the renal tubules, and also by inhibiting conversion of 25(OH)D to 1,25(OH)2D by the kidney,
which in turn causes reduced calcium and phosphate absorption from the gut.
 The presentation is with symptoms and signs of rickets during childhood that do not respond to vitamin D
supplementation.
 In adults, hypophosphataemic rickets may be accompanied by dental abscesses, and by bone and joint pain due to the
development of an enthesopathy.

45. Investigations:
 low serum phosphate levels and a reduction in tubular reabsorption of phosphate.
 Serum levels of vitamin D are normal
 PTH is normal or slightly elevated.
 Serum concentrations of FGF23 are markedly elevated.
 The causal mutation can be defined by genetic testing.

46. Management:
 phosphate supplements (1–4 g daily)
 1-α-hydroxyvitamin D (1–2 μg daily) or 1,25-dihydroxyvitamin D (0.5–1.5 μg daily)
 Levels of calcium and phosphate, as well as renal function, should be monitored regularly
 Recently, a neutralising antibody to FGF23 has been developed that can reverse the biochemical abnormalities in
hereditary hypophosphataemic rickets.

47. Tumour-induced Osteomalacia:
 Rare syndrome caused by over-production of FGF23 by mesenchymal tumours.
 The presentation is with severe osteomalacia and hypophosphataemia in an adult patient with no obvious predisposing risk
factor for vitamin D deficiency
 Biochemical findings are similar as hereditary hypophosphataemic rickets.
 Medical management is with phosphate supplements and active vitamin D metabolites but the treatment of choice is
surgical resection of the primary tumour.

48. Hypophosphatasia:
 Autosomal recessive disorder caused by loss-of-function mutations in the TNALP gene, which result in accumulation of
pyrophosphate and inhibition of bone mineralisation.
 Chondrocalcinosis may also occur.
 The typical presentation is with severe intractable rickets during infancy, sometimes in association with seizures.
 Heterozygous carriers of mutation in TNALP may present in adulthood with osteoporosis, fractures and low ALP values.

49.  Investigations show low or undetectable levels of serum ALP but normal levels of calcium, phosphate, PTH and vitamin D
metabolites.
 Urinary excretion of pyridoxal 5′ phosphate and phosphoethanolamine (substrates for ALP) is increased.
 remarkable therapeutic responses have been obtained with recombinant ALP therapy (asfotase alfa), which is curative.
 Bisphosphonates should be avoided since they may exacerbate the mineralisation defect.

50. Thank You…