Rickets and Osteomalacia - CABRINI PDF

RICKETS and OSTEOMA LACIA Carolyn Narvacan – Montano, MD, FPCP, FCEDM  OUTLINE RICKETS BONE 01 vs 02 REMODELLING OSTEOM MINERALIZATIO PATHOGE ALACIA Clinical N 03 NESIS 04 manifestati...

RICKETS and OSTEOMA LACIA Carolyn Narvacan – Montano, MD, FPCP, FCEDM  OUTLINE RICKETS BONE 01 vs 02 REMODELLING OSTEOM MINERALIZATIO PATHOGE ALACIA Clinical N 03 NESIS 04 manifestati ons GENETIC 05 treatme 06 DISORD nt ERS 0 1 RICKETS vs osteomal acia rickets specific bone disorder of the growing skeleton occurring only in children and adolescents before the epiphyseal fusion has occurred  RICKETS vs osteomalacia RICKETS OSTEOMALACIA specific bone disorder of the growing skeleton generalized softening of the bones regardless of only in children and adolescents before age or cause epiphyseal fusion Occurs in both children and adults defective mineralization of both preosseous defective mineralization of the mature carti- lamellar bone laginous and mature osseous matrix resulting in subnormal linear growth, a consequence of the involvement of growth plates FGF-23 an essential regulator of normal phosphate and 1,25(OH)2D3 homeostasis. Increased by Phosphate and 1,25(OH)2D3 acts on the renal proximal tubule to suppress synthesis of 1,25(OH)2D3 and to decrease the reabsorption of phosphate. 02- BONE REMODELIN G AND MINERALIZA TION Bone remodeling and mineralization  Bone remodeling and mineralization For proper and optimal mineralization of the bone 2 criteria must be met: ○ Synthesis of lamellar bone matrix by osteoblast ○ Exposure of this matrix to optimal Ca x P product Difference of classical osteomalacia from osteomalacia like osteoid accumulation ○ Classical Osteomalacia has defective mineralization due to lack of minerals ○ Hypophosphatasia – enzyme deficiency ○ Fibrous dysplacia, Pagets disease of the bone, fibrogenesis imperfecta ossium, osteogenesis imperfecta – due to  Bone remodeling and mineralization Normal mineralization of bone matrix occurs in two stages. 1. Primary Mineralization - the rapid phase - 75% to 80% of the maximal mineral content is deposited within a few days to weeks. 2. Secondary Mineralization - much slower phase - the mineral content of the bone increases further to reach about 90% to 95% over a period of months. - The remaining 5% to 10% represents the bone matrix that is newly formed but not yet mineralized  Bone remodeling and mineralization Hyperosteoidosis osteoid surface greater than 15% of the bone surfaces can be seen in conditions with high rates of bone turnover, such as immediately after estrogen depletion in post-menopausal women, hyperparathyroidism (primary or secondary), hyperthyroidism, and osteitis deformans. do not conform to the classical definition of osteomalacia  Definition and histologic evolution of osteomalacia Hypovitaminosis D Increased bone Associated with Osteopathy Stage I remodelling due to increased osteoid Normal Mineralization earlies bone phenotype of Vitamin (HVO I ) or Pre secondary hyperparathyroidism surface and volume but no thickness D Deficiency osteomalacia Further accumulation symptomatic- with HVO II of osteoid surface , bone pain, muscle Hypocalcemia volume and weakness and fragility Hypovitaminosis II THICNESS or pseudo fractures Mineralization HVO III CEASES Invariable hypocalcemia Hypovitaminosis III Osteoid accumulation continues pathogenesi s  PATHOGENESIS Vitamin D Phosphate Depletion or Depletion of Deficiency Deficiency Calcium Depletion or Deficiency  PATHOGENESIS 3 Principal mechanisms: 1. Vitamin D Depletion Or Deficiency Extrinsic – deficiency; poor dietary intake decreased sunlight exposure, or defective 25 hydroxylase in the liver or 1 alpha hydroxylase in the kidney, Intrinsic – depletion – impaired GI absorption of vit D (most common cause of osteomalacia) from intestinal disease(osteomalacia from inflammatory bowel disease has not been reported) , resection or gastric bypass, ususal parenchymal liver disease are insufficient to cause sufficient vitamin D depletion to cause osteomalcia  PATHOGENESIS 3 Principal mechanisms: 2. Phosphate Depletion Or Deficiency Deficiency – rare maybe due to prolonged parenteral nutrition, iron deficiency phosphate binders Depletion – second most common cause of rickets and osteomalacia, most prevalent type in areas of the world where vit D deficiency is not endemic The 2 most common causes are: ○ Hereditary hypophsophatemic syndromes ○ FGF23 secreting tumors atypical and focal osteomalacia – uncommon toxic effects of NaF, etidronate, aluminum , Fe  PATHOGENESIS 3 Principal mechanisms: 3. Calcium deficiency Only causes rickets but not osteomalacia in nutritional hypocalcemia without associated vit D deficiency Short latency disease – severe 2o HPT from severe calcium deficiency in children produces rickets Long latency disease- mild 2o HPT over long period of time produces osteoporosis A daily calcium intake of >200 mg/day is the lowest threshold for the risk of developing calcium deficiency rickets independent of vit D status Occurs later in life with an average age of 4 years Clinical manifestati ons  Clinical manifestations The most common manifestations are: ○ Bone pain Diffuse non-descript dull and aching deep seated and poorly localized Often bilateral and symmetric Rarely relieved by rest Begins at the lower back and spreads to the hips, thighs, upper back and pelvis Rarely felt below the knee unless fragility or pseudo fractures are present Propensity to localize at axial skeleton due to greater accumulation of osteoid in cancellous bone vs appendicular bones which are rich in cortical bones More common in vit D deficiency osteomalacia  Clinical manifestations ○ Muscle weakness and difficulty in walking Proximal muscle especially in the lower extremities DTR are usually normal or increased which helps distinguish osteomalacia from other types of muscle disease and myopathies More common in hypophsophatemic rickets and osteomalacia In X- linked hypophosphatemia despite significant muscle weakness bone mass, size and strength are normal or increased.  Clinical manifestations The most common manifestations are: ○ Skeletal Deformities and fractures: Common in rickets but uncommon in adult onset osteomalacia Infants: Open fontanelles, dolichocephaly, frontal bossing rachitic rosary Harrison Sulcus – horizontal line of depression at the level of diaphragm due to chest muscle weakness Once starts walking: Genu valgum, genu varum bowing of long bones and windswept deformity Looser zones or Pseudofractures – diagnostic radiologic abnormality: radiolucent bands perpendicular to the long axis of bones, are stress fractures that can extend to complete fracture usually in the subtrochanteric region of the femur and metatarsals  Biochemical changes Elevated alkaline phosphatase is the most frequent and earliest biochemical abnormality Hypocalcemia is a late biochemical manifestation Phosphate level is variable and non-specific ○ Can be low, normal or high especially in patients with severe hypercalcemia ○ Serum Phosphate 30 ng/ml ○ Target PTH – normal range VITAMIN D DEPENDENT RICKETS Vitamin d dependent rickets are due either to a defective 25-hydroxyvitamin D 1α- hydroxylase, the critical enzyme required in the final step of vitamin D biologic activation VDDR2 – have alopecia, a unique feature that distinguishes from VDDR1a and VDDR1b Hereditary hypophosph atemic rickets and osteomalaci  Hereditary hypophosphatemic rickets and osteomalacia Vitamin D resistant rickets AUTOSOMAL DOMINANT HYPOPHOSPHATEMIC RICKETS ○ Mutation in FGF23 gene (Arg 176, Arg 179 resistance to proteolytic processing) AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIC RICKETS ○ Type 1 –Dentin matrix protein mutation (DMP1) Presents in childhood with leg deformities and short stature ○ Type 2 – Ectonucleotide pyrophosphatase/phosphodiesterase mutation (ENPP1) ○ ARHR typically manifests during childhood with clinical features of rickets ○ In adulthood ARHR patient may present with bone pain muscle weakness and repeated fractures  Hereditary hypophosphatemic rickets and osteomalacia X-linked Recessive Hypophsophatemic Rickets (Dents disease Complex) ○ Xp11.22, X25 ○ Characterized by proximal renal tubular resorptive disorder of the Fanconi type ○ 2 types: Type 1 - 50-60% of cases due toinactivating Cl channel 5 mutation (CLCN5) that codes for chloride proton exchanger Type 2 – 15% of cases – inactivating mutations of oculocerebrorenal syndrome gene (OCRL) that codes for inositol polyphosphate 5 phosphatase ○ Only type of genetic Rickets associated with nephrocalcinosis and nephrolithiasis  Hereditary hypophosphatemic rickets and osteomalacia X-Linked Hypophsophatemic rickets and Osteomalacia ○ Due to PHEX inactivating mutation (regulates FGF23 proteolysis) ○ Most common hypophsophatemic rickets ○ The distinguishing clinical manifestation is enthesopathy which is exclusive to XLH  Hereditary hypophosphatemic rickets and osteomalacia Radiologic and biochemical findings ○ Metephyseal involvement is slightly asymmetrical and bowing is slightly more common ○ Adult patients are obese and short with greater shortening of the lower extremities ○ The most common and consistent biochemical finding is hypophosphatemia, renal phosphate wasting low TmP/GFR ○ Elevated alkaline phosphatase ○ Calcium 25 OH vit D and PTH are normal ○ FGF 23 is inappropriately elevated in the context of hypophosphatemia  Hereditary hypophosphatemic rickets and osteomalacia Treatment: ○ Active vitamin D metabolites and oral phosphate supplementation Reduces pain and manages symptoms but does not reverse or prevent ethesopathy in XLH May develop hypercalciuria and nephrocalcinosis and impaired renal function May cause secondary hyperparathyroidism ○ Burosumab – Anti FGF 23 IgG antibody Unclear if it will have long lasting effects on radiologic and clinical rickets and osteomalacia Tumor induced osteomalaci a Tumor induced osteomalacia Paraneoplastic syndrome presenting as bone pain profound muscle weakness and fractures Produces FGF 23 Often caused by small mesenchymal tumors ○ half are found in the skeleton the remaining are in soft tissues Biochemical features include: ○ Hypophosphatemia (