It encompasses the endocrinological approach to Rickets and possible management options

1. Approach to Rickets: Its
management
Dr. Shinjan Patra

2. Introduction
• Rickets is due to defective mineralization of both
pre-osseous cartilaginous and mature osseous
matrix resulting in subnormal linear growth, a
consequence of the involvement of growth plates
• Osteomalacia is due to defective mineralization of
the mature lamellar bone
• Historically thought to be only due to vit-D
deficiency but currently FGF-23 mediated
mechanisms lead to vit-d resistant rickets coming
out to be an important mechanisms

3. Major metabolic bone diseases
• Of the four major metabolic bone diseases-
Osteoporosis is by far the most common
Rickets and osteomalacia combined are a distant
second
Followed by Paget disease of bone
Osteitis fibrosa cystica, the typical bone disease
of severe primary, secondary, or tertiary
hyperparathyroidism, is the least common,

5. History
• The earliest reports of rickets date back to the
17th century, with the first detailed
contemporaneous descriptions by William
Glisson and Daniel Whistler in 1645
• The temporal relationship between rickets and
sunshine was not appreciated until the 19th
century and the “proof of concept” that sunshine
can cure rickets did not occur until the beginning
of the 20th century

8. Epidemiology
• The most recent estimates of vitamin D–deficiency rickets
ranged from 2.2 in 100,000 people in 1980 to 24 in 100,000
people currently
• The prevalence of osteomalacia in adults due to vitamin D
depletion may be rising because of the increasing rates of
bariatric surgery for morbid obesity, which results in
malabsorption of both vitamin D and calcium
• Rarity of vitamin D deficiency rickets and osteomalacia in
developed countries explains the relatively higher
prevalence of genetic and acquired forms of rickets and
osteomalacia in the Western world

9. • Thus, rickets and osteomalacia not related to
nutrition and drugs are most prevalent in the
developed countries
• Whereas rickets and osteomalacia related to
vitamin D and calcium deficiency are most
common in developing countries

10. Ekbote VH, Khadikar AV, Mughal MZ, Hanumante N, Sanwalka N, Khadikar VV et al. Sunlight exposure and development of rickets in Indian toddlers. Indian J Pediatr. 2010;77:61–5.
doi:10.1007/s12098-009-0263-2
Jain V, Gupta N, Kalaivani M, Jain A, Sinha A, Agarwal R. Vitamin D deficiency in healthy breastfed term
infants at 3 months & their mothers in India: seasonal variation & determinants. Indian J Med Res.
2011;133:267–73.
Chabra T, Tahbildar P, Sharma A, Boruah S, Mahajan R, Raje A. Prevalence of skeletal deformity due to nutritional rickets in children between 1 and 18 years in tea garden community. J
Clin Orthop Traum2016;7:86–9. doi:10.1016/j.jcot.2016.01.005.

11. Bone remodeling
• In the course of normal bone remodeling, a moiety of old
bone is removed and replaced by the same amount of
normal lamellar bone in young adults, but in aging and
disease, the replacement mechanism is not as efficient as it
is in the young
 By a lesser amount of normal lamellar bone replaced in
osteoporosis
 By an un-mineralized bone matrix (or osteoid tissue) in
osteomalacia
 By a mixture of woven bone and fibrous tissue in
hyperparathyroidism,
 By an abnormal local production of woven bone in paget’s

12. Pathogenesis

13. Stages
• 1st stage: Characterized by an increased bone remodeling due to
2°HPT, associated with increased osteoid surface and osteoid
volume, but not the thickness of osteoid, and normal mineralization
of bone
• 2nd stage: Further accumulation of osteoid with increases in osteoid
surface, osteoid volume, and osteoid thickness but with
preservation of some mineralization
 Both serum PTH and alkaline phosphatase levels increase further,
but serum 1,25-dihydroxyvitamin D levels may return to normal or
low depending on the degree of vitamin D deficiency
• 3rd stage: Mineralization of bone matrix ceases and osteoid
accumulation continues to cover more than 90% of the bone
surfaces
 Patients are almost always symptomatic at this stage

15. Consequences of hypophosphatemia
• first occurs locally around osteoblasts and
chondrocytes, leading to the accumulation of
hypertrophic chondrocytes in the growth plate
• producing muscle weakness, tenderness and pain
• hydration and swelling of the de-mineralized collagen
matrix, which causes the periosteal covering to expand
outward
• ultimately resulting in bone deformity and bone pain
• Vitamin D deficiency in combination with
hypocalcaemia may manifest clinically as wheezing,
hypotonia, muscular weakness, brisk reflexes and
cardiomyopathy

16. Difference between healthy & rickets
Normal/Healthy Rickets
cartilage cells in the resting zone of the
growth plate mature into
chondrocytes, and this occurs
progressively from the epiphysis to the
metaphysis
Then, these chondrocytes
are organized into columns, aligned along
the longitudinal axis, and undergo
hypertrophy
leads to a loss in their columnar
arrangement and, therefore,
disorganization of the growth plate
differentiated hypertrophic chondrocytes
are then vascularized
Impaired vascularization
undergo apoptosis Impaired apoptosis
mineralized, and
eventually are turned into primary
spongiosa
End result hypertrophy of the
costochondral junctions, swelling at the
end of long bones, and widening of
metaphyses, cortical thinning,
and impaired remodelling

17. Etiologies

21. Clinical manifestations

22. Bone pain
• Characteristics: Diffuse, nondescript, dull aching, deep seated, and
poorly localized and at times can be debilitating
• Location: Felt more in the bones than in the joints and often is
bilaterally symmetric
• D/D: Because of its vague nature, often misdiagnosed as tension
headache (so-called osteomalacic cephalalgia), “angina” (chest pain
due to pseudo-fractures in the ribs) rheumatism and fibromyalgia
• Aggravated by weight bearing or muscle contractions during
attempted walking
• Tenderness can be elicited by pressure or percussion over the shin
bones
• The mechanism believed to be related to the stretching of the
periosteum by the over-hydrated un-mineralized bone matrix.

23. Muscle weakness
• Lower extremities proximal muscle weakness
• In advanced cases, classical waddling gait ; result of a combination
of muscle weakness and bone pain
• With prolonged depletion patient may become completely
immobilized and bed bound because of profound weakness and
excruciating bone pain, sometimes masquerading as a terminal
illness
• Despite profound muscle weakness, muscle atrophy is uncommon,
although mild muscle wasting with atrophy of the type II fibers has
been reported occasionally
• Hypotonia can be present
• DTR normal or increased
• In general, muscle weakness is more prominent in
hypophosphatemic rickets and osteomalacia, whereas bone pain
is more common in vitamin D–deficiency osteomalacia

24. Skeletal deformities & fractures
• Common in children, vary with the age of
presentation and may remain permanent
• Uncommon in adult-onset osteomalacia
• Infants present with open fontanelles,
dolichocephaly, frontal bossing, rachitic rosary,
Harrison sulcus, swollen wrist and ankle joints
• Once the child starts walking, bowing of the long
bones, genu valgum, genu varum and windswept
deformity
• More severe in genetic hypophosphatemic rickets

25. Biochemical changes
• Elevated sALP most frequent (∼80–90%) and the earliest
biochemical abnormality
• Mild to moderate hypocalcemia (serum calcium level of
7.0–8.5 mg/dL): often asymptomatic unless it falls below
the threshold for symptoms (usually <6.0 mg/dL)
• Phosphate in nutritional rickets and osteomalacia can be
normal, low, and occasionally high, particularly in patients
with more severe hypocalcemia
• PTH always elevated in nutritional-deficiency (both vitamin
D and calcium) rickets and osteomalacia, and the levels are
normal in hypophosphatemic disorders regardless of the
pathogenesis, unless vitamin D deficiency also exists

26. Imaging features
• Generalized thinning of cortices in the long bones
is probably the earliest radiologic manifestation
• Generalized decrease in apparent bone density
on x-rays, vertebral deformities and pseudo-
fractures
• Although these latter bone abnormalities may
resolve following vitamin D therapy, cortical
thinning remains permanent and increases the
fracture risk for the remainder of the patient’s life
• Rugger-jersey spine

27. Other features
• With a few exceptions, most radiologic features
are similar among the various type of rickets and
osteomalacia
• Cortical thinning in long bones is not seen in XLH,
and in fact, thick cortices are the rule rather than
the exception
• Similarly enthesopathy is seen exclusively in XLH
• When present, Looser zones are seen as “hot
spots” on nuclear imaging

30. D/d of leg bowings
• Developmental/congenital bowing
• Blount disease
• Osteogenesis imperfecta
• Widening of the growth plate-
• Schmid-type metaphyseal chondrodysplasia
• Hypovitaminosis C
• Delayed maturation due to illness
• Acromegaly
• Hypothyroidism
• Hyperparathyroidism

31. D/d of flaring of metaphysis
• Anemia
• Fibrous dysplasia
• Storage diseases
• Fibrous dysplasia
• Chronic lead poisoning

33. BMD
• Reduced at all of the relevant sites (lumbar
spine, proximal hip, and forearm), usually with
a greater deficit at the site of rich cortical
bones in the forearms
• By contrast, BMD is either normal or even
increased at the lumbar spine in adults with
XLH osteomalacia

35. Diagnostic guidelines
• Japanese society guidelines:
• Definite rickets
 Rachitic changes on radiographs (cupping and fraying of
metaphysis, widening of epiphyseal plate)
 High blood alkaline phosphatase
 Hypophosphataemia or hypocalcaemia
 Clinical signs: bone deformities such as genu varum and valgum,
abnormal spinal curvature, craniotabes, open fontanelles, rachitic
rosary, joint swelling
• Possible rickets
 Rachitic changes on radiographs (cupping and fraying of
metaphysis, widening of epiphyseal plate)
 High blood alkaline phosphatase
 Hypophosphataemia hypocalcaemia or clinical signs

37. Treatment basic points
• Patient symptom relief is much faster (a few weeks to a
few months) than the biochemical, radiologic or
histologic improvements, which may take a few
months to years
• Even after apparent “cure” of clinical, biochemical,
radiologic and bone histologic abnormalities, many
patients remain at risk for fractures because of
irreversible cortical bone loss
• Accordingly, the goals of therapy are not only to simply
relieve symptoms but also to restore bone strength by
mineralizing the excess osteoid and prevent bone loss
by correcting 2°HPT

38. Dosage
• In symptomatic patients with moderate to severe rickets and
osteomalacia, it’s recommended 50,000 IU of either ergocalciferol
(vitamin D2) or cholecalciferol (vitamin D3) weekly for 8 to 12
weeks followed by a maintenance dose of 1000 to 2000 units daily
• During follow-up, adjustments to the vitamin D dose should be
made based on serum and urine levels of calcium, alkaline
phosphatase, PTH, and achieved serum 25-hydroxyvitamin D levels,
with target levels of 25-hydroxyvitamin D greater than 30 ng/mL
and PTH in the reference range
• Once achieved, a maintenance dose of 1000 to 2000 IU/day is
recommended

39. • Use of calcitriol along with vitamin D is suggested in
patients with more severe 2°HPT (PTH levels >500 pg/mL),
in some patients with significant malabsorption of calcium
due to celiac sprue or gastric bypass surgery, in patients
with documented bone marrow fibrosis
• In malabsorptive states, particularly in patients with small
intestinal resection or gastric bypass surgery, higher doses
of vitamin D (10,000–50,000 IU/day) may be required
• Compared with parenteral administration, the rise in serum
25-hydroxyvitamin D levels is rapid with oral preparations
• May unmask underlying primary hyperparathyroidism
• Oral calcium supplements in the form of calcium carbonate
(or citrate) 1000 to 1500 mg/day in divided doses

40. Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K et al. Global consensus recommendations on prevention and management of
nutritional rickets. Horm Res Paediatr. 2016;85:83–106.
doi:10.1159/000443136
on

41. VDDR2 compare to VDDR1
• Children with VDDR2 have alopecia, a very
unique feature that distinguishes VDDR2 from
both VDDR1A and VDDR1B
• However, the prevalence of alopecia is
variable as is its extent of involvement ranging
from alopecia of the head to alopecia of the
entire body ‘alopecia universalis’

42. Vit-D dependent rickets
• Both VDDR1A and VDDR1B respond to
physiologic replacement doses of calcitriol
(0.04 μg/kg per day), just as nutritional rickets
• However, patients with VDDR2 require much
higher doses of vitamin D or calcitriol because
of end-organ resistance as a result of vitamin
D receptor defects

43. ADHR/ARHR
• ADHR caused by activating mutation in FGf-23
• Whereas inactivating mutations in the Dentin matrix protein
(DMP1) and the Ectonucleotide
pyrophosphatase/phosphodiesterase 1 (ENPP1) genes are
responsible for autosomal recessive hypophosphatemic rickets
(ARHR) type 1 and type 2 respectively
• Degree of hypophosphatemia correlates with the intact FGF23
levels
• Deformities of the legs and short stature in childhood, similar to the
clinical phenotype of nutritional rickets
• ARHR typically manifests during childhood with characteristic
clinical features of rickets
• However, in adulthood, ARHR patients may manifest with bone
pain, fatigue, muscle weakness, and repeated bone fractures

44. XLHR (recessive) /Dent’s disease
• Mis-sense, non-sense, frameshift and splicing mutations in genes
located on the chromosome Xp11.22 and X25
• Two subtypes
 Type 1 (∼50–60% of cases): Inactivating mutations in the chloride
channel 5 (CLCN5) gene that codes for a chloride-proton exchanger
 Type 2 (∼15% of cases) : Inactivating mutations in the
oculocerebrorenal syndrome (OCRL) gene located on an X
chromosome that codes for inositol polyphosphate 5-phosphatase
OCRL-1
• Dent disease associated with hypercalciuria with variable other
proximal renal tubular dysfunction, nephrocalcinosis or
nephrolithiasis, low-molecular-weight proteinuria, and progressive
renal insufficiency, but only a minority of patients manifest rickets

45. XLHR dominant
• X-linked dominantly inherited disorder with an
estimated prevalence of about 1 in 20,000 live births
• Inactivating mutation in the phosphate-regulating gene
with homologies to endopeptidases on the X
chromosome (PHEX)
• >300 types of mutations reported
• C/F variable, with most patients presenting with rickets
during childhood
• In childhood-onset XLH, skeletal deformities such as
bowed legs and short stature are common
• In adults, XLH may be discovered during a routine
biochemical work-up

46. Radiological features
• Similar to those seen in nutritional rickets, except
metaphyseal involvement is slightly asymmetrical
and bowing is slightly more common
• As adults, most patients are obese and manifest a
disproportionate short stature with greater
shortening of the lower extremities
• Enthesopathy occurs almost exclusively in XLH
and is almost never seen in other types of rickets
and osteomalacia

49. Biochemical features
• The most common and consistent biochemical
findings are hypophosphatemia
• Renal phosphate wasting as assessed by tubular
reabsorption of phosphate or tubular maximum
for phosphate reabsorption adjusted for
glomerular filtration rate (GFR; TmP/dlGFR)
• Elevated sALP levels
• Ca, 25 (OH) D and PTH levels are characteristically
normal in the untreated state

51. Standard treatments
• Combination of active vitamin D metabolites (calcitriol or
alphacalcidol) and oral phosphate supplementation
• recommend an initial dose of 20–60 mg/kg body weight daily (0.7–
2.0 mmol/kg daily) of elemental phosphorus in infants and
preschool children, which should be adjusted according to the
improvement of rickets, growth, alkaline phosphatase (ALP) and
parathyroid hormone (PTH) levels
• recommend phosphate supplements should be taken as frequently
as possible, for example, 4–6 times daily in young patients with high
ALP levels. The frequency can be lowered to 3–4 times daily when
ALP has normalized (grade B,
• Skeletal deformities and growth retardation may improve with
treatment but do not completely resolve
• In adults, these same medications are used for symptom
management and to improve impaired bone mineralization

52. • recommend a progressive increase in the dose of phosphate
supplements in cases of insufficient clinical response but avoidance
of doses >80 mg/kg daily (based on elemental phosphorus) to
prevent gastrointestinal discomfort and hyperparathyroidism. If
these adverse effects are present, treatment should be adjusted by
decreasing the dose and/or increasing the frequency (grade C
• To prevent nephrocalcinosis, we recommend keeping calciuria
levels within the normal range and avoiding large doses of
phosphate supplements; we suggest measures that decrease
urinary calcium concentration, excretion and/or crystallization if
necessary, including regular water intake, administration of
potassium citrate and limited sodium intake
• phosphate should be given as frequently as possible, for example,
4–6 times per day in young patients with high ALP levels, to
maintain stable blood levels. Less frequent dosing (2–3 times daily)
might improve adherence in adolescents

53. Novel T/t
• Burosumab, a recombinant human immunoglobulin G1 monoclonal
antibody that binds to the FGF23 receptor and inhibits its activity
• With a single dose, burosumab increased the TmP/GFR, and serum
levels of phosphate and 1,25-dihydroxyvitamin D
• Starting dose of 0.4 mg/kg body weight to 0.8 mg/kg body weight,
respectively, given every 2 weeks
• dose should be titrated in increments of 0.4 mg/kg body weight
• maximum dosage of 2.0 mg/kg body weight (maximum dose 90 mg
• The peak serum phosphate concentration achieved was between 8
and 15 days and returned to the baseline within 50 days after the
initial subcutaneous injection

54. Long term management
• Hypercalciuria with or without hypercalcemia
may develop and may lead to nephrolithiasis,
nephrocalcinosis, and impaired renal function
• Use of oral phosphate supplements causes
diarrhea and abdominal pain, which in turn
leads to poor medication adherence
• An unintended consequence of long-term
(usually years) oral phosphate therapy is the
development of 2°HPT

55. • Recommended that any first- generation family member of a
patient with XLH should be investigated for XLH (grade D); sons of
males affected by XLH are not at risk
• Renal Fanconi syndrome) should be excluded by looking for
abnormal bicarbonate, amino acid, glucose and/or uric acid losses
in urines and low molecular mass proteinuria (grade B
• Recommend confirming the clinical diagnosis of XLH by genetic
analysis of the PHEX gene in children and adults if feasible (grade B,
• recommend other causes of hereditary or acquired
hypophosphataemia be considered if analysis of the PHEX gene
yield a negative result for XLH

57. Tumour induced osteomalacia
• first “proof of concept” was provided by Andrea Prader in 1959,
who postulated the production of a “rachitogenic substance” by a
“giant cell reparative granuloma of bone
• rare paraneoplastic syndrome that clinically manifests with diffuse
nonspecific bone pain, profound muscle weakness, and fractures
• biochemical hallmark of TIO is the triad of hypophosphatemia due
to renal phosphate wasting, inappropriately low or normal serum
1,25-dihydroxyvitamin D level, and elevated or inappropriately
normal serum FGF23 level
• FGF23 inhibits both sodium-dependent phosphate reabsorption
and 1α-hydroxylase activity in the proximal tubule, leading to
hypophosphatemia and aberrant production and inappropriately
low levels of 1,25-dihydroxyvitamin D

58. • usually caused by tumors of mesenchymal origin, referred to as
phosphaturic mesenchymal tumor of mixed connective tissue
variant, and rarely by other types of tumors, such as osteosarcoma,
giant cell tumor, glomus tumor, small cell carcinom of the lung, and
adenocarcinoma of the colon
• tumors tend to be small (often escaping clinical detection), slow
growing,231 and difficult to localize; about half of the tumors are
located in the skeleton, and the remaining are located in soft
tissues
• other phosphatonins such as frizzled-related protein 4, FGF7, and
matrix extracellular phosphoglycoprotein have been described
• receive various erroneous diagnoses (rheumatologic, malignant,
and even psychiatric) and, consequently, inappropriate treatments
for years before the tumor causing osteomalacia is found

59. Diagnosis
• Once hypophosphatemia is detected and confirmed, further
assessment of the renal tubular handling of phosphate TmP/GFR
• serum levels of calcium, 25-hydroxyvitamin D, and PTH are normal
in TIO, but similar to genetic disorders, 1,25-dihydroxyvitamin D
levels are either inappropriately “normal” or low
• normal serum FGF23 level does not exclude the diagnosis
• A positive family history of rickets or osteomalacia, or presence of
metabolic acidosis, makes TIO unlikely
• Radiologic and radionuclide manifestations of TIO are similar
• enthesopathy is not seen in TIO, but fractures are common
• Histology similar

60. Localisation of the tumour
• Since somatostatin receptors are expressed in many phosphaturic
mesenchymal tumors of mixed connective tissue variant, an
octreotide scan can help with tumor localization in about 50% of
cases, especially when the extremities and skull are involved
• 18F-fluorodeoxyglucose positron emission tomography is quite
sensitive in localizing tumors but can lead to false-positive results
• Gallium-DOTATATE positron emission tomography is an emerging
imaging modality for tumors producing TIO, is now more widely
available, and may be the imaging method of choice
• Functional imaging can be supported by selective venous sampling
with measurement of FGF23

61. T/t
• resection of the tumor, which results in clinical, biochemical,
radiologic, and bone
• Wide surgical resection is essential to avoid tumor recurrence
• Levels of serum phosphate and FGF23, which has a half-life of ∼45
minutes, return to normal rapidly, often within 24 hours, after
tumor resection, but healing of osteomalacia may take several
months
• If the tumors are not readily identifiable, or not amenable to
surgical removal, lifelong medical therapy with oral phosphate and
calcitriol is required. Oral phosphate in three to four divided doses
with meals and calcitriol 0.5 to 1.0 μg/day in divided doses to
maintain serum phosphates level at the lower end of the age-
appropriate reference range is recommended

64. Drug induced osteomalacia
• NRTI’s m/c drug induced rickets/osteomalacia
• Tenofovir the commonest
• Unlike other hypophosphatemic syndromes, serum FGF23 levels are
characteristically normal in NRTI-related hypophosphatemia
• Time of initiation to development is 1 to 26 months
• Prevalence 0.5%
• Exact mechanism not known decreased mitochondrial DNA
replication and impairs molecular transport, vitamin D activation,
and urinary acidification
• Discontinuation promptly reverses
• Other causes leading to improper vit-d action doesn’t require
discontinuation
• This type of bone histologic abnormality is designated as atypical
osteomalacia

66. Conditions resemble
rickets/osteomalacia
• Primary hyperparathyroidism: Any condition
that increases bone remodeling inevitably
increases the extent of osteoid surface
(usually <50% of the bone surface) and by
extension osteoid volume (usually >3–5% of
bone volume), but osteoid thickness, the
hallmark of mineralization defect in traditional
osteomalacia, is always normal (<12 μm)

67. • fibrogenesis imperfecta ossium and axial osteomalacia :
due to abnormal collagen structure
• Hypophosphatasia: easily distinguished by the low serum
alkaline phosphatase levels
• The tongue-like lucent in the metaphyses of the long bones,
especially in the distal femur, is characteristic of childhood
hypophosphatasia
• However, cortical thinning, a feature of vitamin D–
deficiency osteomalacia, is not seen in hypophosphatasia
• The diagnosis is supported by high serum levels of vitamin
B6, pyridoxal phosphate, and inorganic pyrophosphate