Ppt Approach to Rickets and it's Management

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 O steomalacia 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,

4. 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

5. 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

6. 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

7. 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.

8. 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

9. Pathogenesis

10. Stages 1 st 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 2 nd 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 3 rd 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

11. 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

12. 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

13. Etiologies

14. Clinical manifestations

15. 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.

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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 ’

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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 )

48. 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