Rickets - Current Concept Review.pptx

1. RICKETS
OLEH :
Kalih Rahmat Gusti
PEMBIMBING :
dr.Anung Budi Satriadi, Sp.OT(K)
ARTICLE REVIEW

2. INTRODUCTION
1. Background
Rickets epidemics have historically occurred in waves
The use of cod liver oil was an effective remedy during the first wave,
which occurred in the western world during the industrial revolution due
to a lack of sunlight caused by smog.
Vitamin D supplementation reduced the second wave of rickets
Unfortunately, complacency has returned, and a "third wave" of rickets is
currently underway
This is in part due to reduced UVB exposure as a result of modern
lifestyle factors and sun avoidance measures like sunscreen and clothing,
including for cultural reasons

3. INTRODUCTION
1. Background
A defect in the
mineralization of
the epiphyseal
plates is what
causes rickets
passed
down
acquired
common cause :
nutritional
acquired rickets
Asymptomasis,
irritability, growth
retardation, and
sudden death are
all possible
manifestations

4. INTRODUCTION
1. Background
Rickets must be promptly diagnosed and aggressively treated to avoid long-term
complications
Vitamin D deficiency or calcium deficiency in the diet is still the most common
cause of nutritional rickets that may result from improper mineralization
The widening of the epiphyseal plates and a defect in mineralization are
hallmarks of rickets

5. Etiology
Rickets
calcipenic (Ca)
Calcium salt is an organic component of the bone matrix, in
order for bone to mature
This process is slowed down which causes osteoid to
accumulate beneath the growth plate, eventually leading to
bone softening over time
severe nutritional vitamin D deficiency, inability to produce 25-
hydroxyvitamin D (as in liver failure or drug intoxication), or
e.g., phenytoin) or 1,25-dihydroxyvitamin D (such as in chronic
kidney disease) or due to end-organ resistance
phosphopenic
(Pi)
is found in abundance in all body tissues, is an essential
structural component for the mineralization of bone
. Increased phosphate excretion in the kidneys is typically the
cause of it

6. Calcipenic
External
environmental
secular
behavioral
Internal
unique to the
individual
Genes, drug-
induced
rickets
liver diseases
Vitamin D metabolism inhibitors like
diphenylhydantoin and rifampicin
Risk factors for vitamin D and dietary calcium deficiency(Uday and Högler, 2020)

7. Sources and metabolism of vitamin D. PTH, parathyroid
hormone.(Chanchlani et al., 2020)
Parathyroid/bone/kidney axis (Chanchlani et al., 2020)

8. Epidemiology
Asian, Middle
Eastern, and
African
nations
prevalence rates
range = 10 – 70%
widespread
introduction of
dietary vitamin D
supplements
legislation to
improve air
quality
public recognition
of the significance
of vitamin D and
bone health

9. Vitamin D
deficiency
Low serum
phosphate levels
Low serum calcium
level
a low calcium intake
from food
Hyperparatiroidism
phosphaturia
abnormal bone
mineralization
Pathophysiology

10. Diagnostic
Detailed History
• child's gestational age
• specifics regarding sunlight exposure
• dietary history (supplementation, developmental/growth history, and pertinent family history of
skeletal abnormalities, stunted growth, alopecia, dental abnormalities, and parental consanguinity)
Clinical Appearance
• Pay atteinon for any tenderness, deformities, softening, asymmetry, or neurological abnormalities.
Advanced Investigation
• Radiological and Laboratory examination

11. Clinical elements of calcipenic rickets
(Haffner et al., 2022a)
a. An 18-month-old girl with nutritional rickets presented
with genu vara, growth plate widening, and metaphyseal
fraying on X-rays.
b, c. Two infants with rachitic rosary and wrist widening as a
result of utritional rickets, respectively
d. A boy who is 14 years old and has genu valga because of
nutritional rickets
e. Infant with alopecia caused by vitamin D-dependent
rickets type 2A

12. Clinical elements of phosphopenic rickets
(Haffner et al., 2022)
a. 2-year-old boy diagnosed with X-linked hypophosphatemia
(XLH) at the age of 2 years, presenting with disproportionate
short stature (–2.3 SD score), genu vara, and widening of growth
plates and metaphyseal fraying on X-rays
b. 3-year-old patient with XLH started on treat- ment with active
vitamin D and phosphate at the age of 2 years show- ing
disproportionate short stature (height, –2.4 SD score), frontal
bossing, bossing, dolichocephalus and mild signs of rickets on X-
ray.
c. Den- tal abscess on an apparently healthy tooth in a child with
XLH
d. 16-year-old boy with autosomal-recessive hypophosphatemic
rickets type 2 (ARHR2) showing genu vara and mild ricketic signs
on X-ray

13. No Part Findings
1 Skull Craniotabes, or softening of the skull, is a condition that affects infants older than three months. Wide fontanels
and frontal bossing are noted.
2 Chest rosary as a result of the widening of the costochondral junction, pigeon chest, and Harrison's groove, which is a
depression on the lower side of the ribcage caused by the diaphragm pulling on the soft ribcage at its insertion
point
3 Extremiti
es
Deformities of the weight-bearing limbs, most of which involve the rapidly growing bones, may present in the
infant. Upper limb deformities may be present in crawling infants. However, the child's lower limbs show the
deformities when they begin to walk. Bow legs (genu varus), knock knees (genu valgus), and joint swelling (knees
and ankles) are potential lower limb deformities. On the other hand, the wrist widening is a potential upper limb
deformity. Because of its relatively rapid growth, the ulna is significantly affected.
Bone clinical manifestations in rickets
(Dahash and Sankararaman, 2022)
Clinical Appearance

14. No Part Findings
4 Spine kyphosis and deformity of the spine.
5 Other Hypotonia, proximal myopathy, limb fractures, a contracted pelvis that may obstruct labor in adulthood, gait
disturbance, growth retardation, bone softening, bone pain (present as irritability), and bone tenderness are some
of the other conditions that can occur.
Bone clinical manifestations in rickets
(Dahash and Sankararaman, 2022)

16. Algorithmic approach to a child with rickets
(Gentile and Chiarelli, 2021)

19. Management
A study by Mittal et al. (2018)
• 90,000 IU
• 300,000
IU
Comparable
Vitamin D
for Healing
Rickets
• good healing of
rickets
• without any
increased risk of
hypercalcemia
and
hypercalciuria.
90,000 IU • hypervitaminosis D
[S.25(OH)D >150
ng/mL] in 2/43
subjects
• showing complete
healing with
radiographic score
reduced to zero at 12
week 300,000 IU

20. Mittal et al. (2018) conclude that 90,000 IU
vitamin D, single oral dose, is an effective as
well as safe regimen for treatment of nutritional
rickets in Indian children aged <5 years
Stögmann et al. (1985)
compared stoss regime (400,000
IU vitamin D3, given as 200,000
IU orally on day 1 and day 3)
versus continuous treatment
(9,600 IU vitamin D3, daily for 18
days, cumulative dose of 172,800
IU) and found no difference
between the two treatment
groups.
three different therapeutic modes
(single dose of 150,000 IU
intramuscular, single dose of
150,000 IU orally, and oral 5,000
IU/day for 30 days) were compared,
with similar improvement in rickets
(Gultekin et al., 1985)
Özkan et al. (2000) also evaluated the efficiency
of three different therapeutic approaches
(300,000 IU orally single dose, 300,000 IU
intramuscular single dose, and 600,000 IU orally
single dose of vitamin D), and found no
difference in response to treatment among the
groups. However, the group that received
600,000 IU dose had 30% incidence of
hypercalcemia.

21. efficacy of single intramuscular dose of
vitamin D (600,000 IU) with that of an
oral daily dose of vitamin D (2,000 IU)
for 4 weeks in infants with nutritional
rickets. Among those on oral therapy,
40% did not achieve radiographic
healing and this was attributed to poor
compliance (Lubani et al., 1989).
Indian study (Mittal et al., 2014)
evaluated the non-inferiority of
300,000 IU to 600,000 IU oral
vitamin D (administered as single
dose) and demonstrated radiologic
healing in all subjects at 12 weeks.
Soliman et al. (2010) administered
single dose of vitamin D in doses of
10,000 IU/kg intramuscular (up to a
maximum of 150,000 IU) with
radiographic evidence of complete
healing in 95% subjects.
Cesur et al. (2003) did not find any
difference among three doses of
vitamin D (150,000 IU, 300,000 IU,
and 600,000 IU as single oral dose)
in the healing of rickets. However,
hypercalcemia developed in eight
infants, 2/20 who received 300,000
IU dose and 6/16 who received
600,000 IU dose

22. Nugroho et al. (2021) said
the daily tolerable upper
intake level of vitamin D is
4.000 IU
The study assessed the effectiveness of
daily vitamin D supplementation for
subjects with hypovitaminosis D and few
participants blamed the daily
supplementation for their complaints, like
sore throat, sprue, nausea or abdominal
pain, and diarrhea,
higher vitamin D intake (1000 -2000 IU) is
required to achieve and maintain 25(OH)D level
to be more than 30 ng/ ml.
RDA (Recommended Daily
Allowance), the recommended
daily vitamin D dose of 600-800 IU
is needed to optimize bone health

23. The Lawson Wilkins Pediatric Endocrine
Society recommends (WHO 2019)
•Infants younger than 1 month: 1000
IU/day
•Infants aged 1–12 months: 1000–5000
IU/day
•Children older than 12 months: >5000
IU/day
•When the condition is resolved, which
usually occurs 3–4 months after
treatment, a maintenance dose of 400
IU/day is suggested
The Global consensus recommendations
on prevention and management of
nutritional rickets
•Infants younger than 3 months: 2000
IU/day for 12 weeks, with a maintenance
dose of 400 IU until the condition is
resolved;
•Infants aged 3–12 months: 2000 IU/day
for 12 weeks or a single dose of 50 000 IU,
with a maintenance dose of 400 IU until
the condition is resolved;
•Children aged 1–12 years: 3000–6000
IU/day for 12 weeks or a single dose of
150 000 IU, with a maintenance dose of
600 IU until the condition is resolved;
•Children older than 12 years: 6000 IU/day
for 12 weeks or a single dose of 300 000
IU, with a maintenance dose of 600 IU
until the condition is resolved;
•Monitoring of nutritional rickets after the
onset of treatment.
Patients with tumor-induced osteomalacia
should primarily undergo tumor resection
•children with calcipenic rickets require
either supplemental or pharmacological
treatment with native or active vitamin D.
•. If burosumab is available, it should be
used to treat children with X-linked
hypophosphatemia
•Alternatively, children with other types of
fibroblast-growth factor 23 (FGF23)-
associated hypophosphatemic rickets
should get frequent doses of oral
phosphate salts and active vitamin D.
•Because they are associated with
excessive 1,25-dihydroxyvitamin D
production, forms of hypophosphatemic
rickets that are not caused by FGF23 are
treated solely with oral phosphate

24. 1. General Approach
• The underlying etiology of rickets, whether nutritional or genetic, determines the treatment options for the
condition because correction of such a deformity, without controlling the rickets, invariably leads to its
recurrence.
• The primary treatment goal is to correct or at least improve rickets/osteomalacia based on clinical and
biochemical parameters; which clinical assessment includes
– growth parameters (height, weight, calculation of annual height velocity, and head circumference in
infants)
– degree of leg bowing
– gait pattern
– presence of bone pain and muscle weakness
– dental abnormalities.
• Biochemical measures include serum phosphate, calcium, and alkaline phosphatase (ALP) as a surrogate
marker of osteoblast activity and thus degree of rickets, parathyroid hormone (PTH), and 25-
hydroxyvitamin D3 (25(OH)D)

25. 2. Management for Calcipenic Rickets
• Patients should be treated with ergocalciferol (vitamin D2) or cholecalciferol
(vitamin D3) at a minimal dose of 2000 IU (50 μg) per day in conjunction with 500
mg oral calcium per day, either as a dietary intake or supplements, for a minimum
of 3 months.  The latter allows adequate remineralization of the skeleton and
prevents symptomatic hypocalcemia.
• Oral vitamin D treatment is preferable  it was shown to restore 25(OH)D levels
more rapidly than intramuscular treatment
• Single intramuscular injection ranging from 50,000 IU from the age of 3 months
onwards up to 300,000 IU after the age of 12 years, may be used instead of oral
vitamin D  associated with an increased risk of hypercalcemia  Intravenous
calcium gluconate should be given in patients with symptomatic hypocalcemia until
normalization of serum calcium levels

26. 2. Management for Calcipenic Rickets
• The emergency treatment of hypocalcemia focuses mainly on reversing symptoms rather than correcting
serum calcium levels  Severe symptomatic hypocalcemia (seizure, laryngospasm, tetany)  1 to 2 grams
of calcium gluconate should be administered in 10 minutes and repeated in 10 to 60 minutes until
symptoms resolve  monitoring ECG during IV Calcium bolus
– 10 to 20 mL of 10% calcium gluconate diluted in 50 to 100 mL dextrose or normal saline
intravenously over 10 minutes  For persistent symptoms, the bolus can be repeated after 10 to 60
minutes until symptoms resolve.
– Repeat serum calcium measurements 4 to 6 hours after calcium treatment
• Moderate to severe hypocalcemia (ionized calcium <4 mg/dL) without seizure or tetany:
– An infusion of approximately 100 mg/hr of elemental calcium can be given to adults over several
hours
– 4 g calcium gluconate IV over 4 hours corresponds to 1 gram of calcium gluconate (one ampoule, 10
mL of 10% calcium gluconate) for each hour.

27. 2. Management for Calcipenic Rickets
• After stabilization of normocalcemia :
– switched to oral calcium supplementation
• Patients presenting with dilative cardiomyopathy are usually treated with diuretics
and angiotensin-converting enzyme inhibitors and require management by a
pediatric cardiologist.
• Finally, adequate nutritional requirement for vitamin D through diet and/or
supplementation, which is at least 600 IU/day after the age of 12 months, should be
assured after healing of rickets

28. 3. Management for Vitamin D-dependent rickets
(VDDR)
• Vitamin D-dependent rickets type 1A (VDDR1A)
– is due to mutations in CYP27B1, the gene encoding 1-alpha hydroxylase, patients are treated lifelong
with physiologic 1,25-dihydroxyvitamin D (1,25(OH)2D) doses, given twice daily due to its short
half-life.
– alphacalcidiol (1alpha (OH)D) may be commenced which is converted in the liver to 1,25(OH)2D
(calcitriol) and can be given once daily owing to its longer half-life.
– Due to the high calcium demands of the unmineralized skeleton, patients should be treated during the
first 3 to 6 months with 2–5 times higher dosages of active vitamin D than needed during maintenance
treatment.
– In addition, oral calcium supplementation (50 mg per kg body weight per day of elemental calcium) is
recommended during the early phase of treatment to prevent aggravation of hypocalcemia due to bone
remineralization (“hungry bones”).
– Dosages of active vitamin D should be tailored to keep serum PTH and calcium levels in the mid-
normal range

29. 3. Management for Vitamin D-dependent rickets
(VDDR)
• Vitamin D-dependent rickets type 1B (VDDR1B)
– is due to mutations in CYP2R1 resulting in impaired 25-hydroxylation of
vitamin D2 and vitamin D3 to 25(OH)D should be treated with calcidiol (also
called calcifediol or 25-hydroxy-vitamin-D), which bypasses the defect in 25-
hydroxylation, plus supplemental calcium.  The latter should be done as for
VDDR1A patients
– Alternatively, pharmacological dosages of vitamin D2 or vitamin D3 or
physiological doses of calcitriol can be given, again plus calcium
supplementation

30. 3. Management for Vitamin D-dependent rickets
(VDDR)
• Vitamin D-dependent rickets type 2A (VDDR2A)
– is due to mutations in VDR resulting in impaired signaling of the vitamin D
receptor 
– high oral doses of calcium (5–6 g/m2 body surface area of elemental calcium)
are usually sufficient to restore normocalcemia and normalize PTH levels
during the first few months of life in infants with VDDR2A
– some patients require primary intravenous calcium infusions to adequately
raise serum calcium  Calcium infusions need to be continued until the
“hungry bone syndrome” is cured, i.e., the point at which oral calcium
supplementation allows normocalcemia to be maintained.

31. 3. Management for Vitamin D-dependent rickets
(VDDR)
• Vitamin D-dependent rickets type 2A (VDDR2A)
– is due to mutations in VDR resulting in impaired signaling of the vitamin D
receptor 
– high oral doses of calcium (5–6 g/m2 body surface area of elemental calcium)
are usually sufficient to restore normocalcemia and normalize PTH levels
during the first few months of life in infants with VDDR2A
– some patients require primary intravenous calcium infusions to adequately
raise serum calcium  Calcium infusions need to be continued until the
“hungry bone syndrome” is cured, i.e., the point at which oral calcium
supplementation allows normocalcemia to be maintained.

32. 3. Management for Vitamin D-dependent rickets
(VDDR)
Suggested vitamin D dose for maintenance treatment of patients with VDDR (Haffner et al., 2022)

33. 3. Management for Vitamin D-dependent rickets
(VDDR)
• Vitamin D-dependent rickets type 2B (VDDR2B)
– is due to mutations in HNRNPC also resulting in impaired signaling of the
vitamin D receptor.
– Therefore, treatment of VDDR2B patients should be similar to that of
VDDR2A patients

34. 3. Management for Vitamin D-dependent rickets
(VDDR)
• Vitamin D-dependent rickets type 3 (VDDR3)
– is due to mutations in CYP3A4 leading to enhanced inactivation of calcitriol

35. 4. Management for Phosphopenic rickets
• X-linked hypophosphatemia (XLH)
– is due to mutations in PHEX resulting in increased expression of FGF23 in
bone and consecutive renal phosphate wasting and reduced calcitriol levels, as
well as other so far poorly understood alterations
– Patients with XLH can either be treated with oral supplements of inorganic
phosphate salts in combination with active vitamin D (“conventional
treatment”) or with burosumab
– Burosumab has several advantages over conventional treatment
• It removes the burden of medicating many times a day, which markedly hampers adherence during conventional treatment
• It was shown to be more effective in healing rickets
• It has a very good profile—whereas conventional treatment is associated with side-effects such as gastrointestinal
discomfort, hypercalciuria, secondary hyperparathyroidism, diarrhea, and nephrocalcinosis

36. 4. Management for Phosphopenic rickets
Daily doses for phosphate and active vitamin D (conventional treatment) in children with X-linked
hypophosphatemia (XLH) and tumor-induced hypophosphatemia (TIO)

37. 4. Management for Phosphopenic rickets
Burosumab treatment in children with X-linked hypophosphatemia (XLH) and tumor-induced hypophosphatemia (TIO)

38. 5. Management for Genetics Rickets
a. A pediatric endocrinologist and/or metabolic bone specialist are best suited to treat the genetic conditions that
cause rickets.
b. Calcitriol, also known as 1,25-dihydroxyvitamin D, is used to treat both vitamin D-dependent rickets type I A
(VDDR1A) and type D-dependent rickets type I B (VDDR1B).
c. High doses of calcitriol and calcium are used to treat vitamin D-dependent rickets type II A (VDDR2A) and type
D-dependent rickets type II B (VDDR2B). A high dose of intravenous calcium is part of the long-term treatment.
d. Familial hypophosphatemic rickets is treated with oral phosphate supplementation alongside vitamin D as
calcitriol or alfacalcidol (1α-hydroxycholecalciferol).
e. If burosumab is available, children with X-linked hypophosphatemia should be treated with it or with frequent
oral phosphate salt doses and active vitamin D, as with other forms of FGF23-associated hypophosphatemic
rickets.

39. 6. Conventional Treatment
• The starting dose of phosphate amounts to 20–60 mg/kg/day (0.7–2.0 mmol/kg per day) based on
elemental phosphorus, given at least four times a day  Dosages should be adjusted according to
clinical and biochemical responses
• High doses (> 80 mg/kg per day) are associated with gastrointestinal side effects (diarrhea,
abdominal discomfort) and secondary hyperparathyroidism
• Treatment with phosphate should always be done in combination with active vitamin D (either with
calcitriol or alphacalcidiol) in XLH patients, as this prevents the development of secondary
hyperparathyroidism as seen in patients treated with phosphate salts alone, which further promotes
renal phosphate wasting and can result in autonomous (tertiary) hyperparathyroidism
• The starting doses of calcitriol and alphacalcidiol amount to 20–30 ng/kg body weight and 30–50
ng/kg body weight daily
• Alternatively, calcitriol and alphacalcidiol may be empirically started at 0.5 μg and 1 μg per day in
patients aged above 12 months.

40. 7. Burosumab Treatment
• Burosumab has been approved by the European Medicines Agency (EMA), the US Food and Drug
Administration (FDA), and Japanese health authorities for treatment of pediatric XLH patients aged
above 12 months (> 6 months in the USA), showing radiographic evidence of bone disease and
with growing skeletons.
• European XLH guideline recommends : “radiographic evidence of overt bone disease; disease that
is refractory to conventional therapy; complications related to conventional therapy; or patient’s
inability to adhere to conventional therapy, presuming that adequate monitoring is feasible”
• The recommended starting dose of burosumab in children amounts to 0.8 mg/kg body weight. It
should be given in 2-weekly intervals as subcutaneous injections.
• Burosumab should be titrated in 0.4 mg/kg increments to raise fasting serum phosphate levels into
the lower end of the normal reference range for age with a maximal dose of 2.0 mg/kg body weight
(maximum dose 90 mg)

41. 8. Adjunctive Treatment
• half of all XLH patients show persistent short stature despite adequate conventional or
burosumab treatment  treatment with recombinant human growth hormone (rhGH)
increases growth rates and standardized height in short children with XLH.
• in a small randomized clinical trial, near-final height did not significantly differ between
rhGH-treated XLH patients and controls  not recommended

42. 9. Surgical Management
• So far, no long-term data on the need for surgical corrections in XLH patients treated
with burosumab are available.
• Children with persistent leg deformities  undergo thorough assessment by an
experienced pediatric orthopedic surgeon on the need and optimal timing for surgical
treatment, i.e., corrective osteotomies versus epiphysiodesis.
• The latter technique requires remnant growth potential and should be performed at least
2–3 years before the end of skeletal growth.
• When the deformity is not clearly due to active rickets with vitamin D deficiency, it can
be called “rickets-like” bone deformity  Temporary hemi-epiphysiodesis can be
performed using staples, percutaneous transphyseal screws, or a tension band plate.
These techniques function by tethering one side of a growing physis, thereby allowing
differential growth (guided growth technique).

43. 10. Dental Care
• Pediatric XLH patients are prone to developing spontaneous dental abscesses causing
pain and swelling in deciduous as well as in permanent teeth, due to poorly mineralized
dentin
• Adolescent and adult XLH patients may develop significant periodontitis which may
cause tooth loss
• Treatment with oral phosphate and active vitamin D was shown to improve dentin
mineralization, and to reduce the frequency of complications, i.e., dental abscesses and
periodontitis

44. PROGNOSIS
• The severity and cause of rickets determine the prognosis
• On the other hand, most genetic causes of rickets cannot be cured, so treatment focuses
on symptom management to improve quality of life and manage complications
• The quality of life (QOL) of adults with osteomalacia and children with rickets can be
significantly impacted by limb deformities and pain
• Due to bone pain, muscle weakness, and, in the case of phosphopenic rickets, pain and
decreased physical function caused by enthesopathy, arthritis, and spinal stenosis, rickets
can ultimately hinder daily activities

45. COMPLICATION
• Poor linear growth, osseous deformities, multiple pathological fractures, hydrocephalus,
increased intracranial hypertension (ICH), and abnormal dentition are potential
complications of the condition if it is not treated.
• Hypocalcemia that doesn't go away can cause problems like skeletal and cardiac
myopathy, seizures, and even death

46. THANK YOU