13 4
5.2 Stepwise Analysis
The index patient presented with fragility fracture at a young age along with prox-
imal muscle weakness. The clinical possibilities with this symptomatology
include primary hyperparathyroidism (PHPT), severe osteomalacia with second-
ary hyperparathyroidism, hypophosphatemic osteomalacia, and renal tubular aci-
dosis. Secondary osteoporosis due to Cushing’s syndrome and hyperthyroidism
can also result in fragility fracture along with proximal muscle weakness. PHPT
is less likely in the index patient as she did not have symptoms related to hyper-
calcemia (painful bones, abdominal groans, renal stones, psychic moans, and
fatigue overtones) and had normal calcium profile, which excludes this diagnosis.
However, the patient had elevated serum iPTH level in the presence of 25(OH)D
sufficiency, which can be explained by concurrent stage 3 chronic kidney disease.
Severe osteomalacia due to vitamin D deficiency usually presents with bone pains
and myopathy. Presence of Looser’s zone, raised alkaline phosphatase, and high
iPTH further supports the diagnosis of vitamin D deficiency. However, osteoma-
lacia to manifest as fracture is very rare and presence of normal calcium and
phosphate levels, with normal 25(OH)D at presentation in the index patient, make
this diagnosis unlikely. Further, hypokalemia is not a feature of vitamin D defi-
ciency-related osteomalacia. Celiac disease is an important consideration in this
scenario, as it may manifest with osteomalacia/osteoporosis as a monosymptom-
atic presentation. Absence of gastrointestinal symptoms and negative celiac serol-
ogy make this diagnosis unlikely. Hypophosphatemic osteomalacia manifests
with bone pains, proximal myopathy, and severe hypophosphatemia, normal or
mildly elevated alkaline phosphatase and iPTH. The index patient had bone pains
and proximal myopathy, but normal serum phosphate and moderately elevated
alkaline phosphatase and iPTH do not support the diagnosis of hypophosphatemic
osteomalacia. Secondary osteoporosis due to Cushing’s syndrome and hyperthy-
roidism, as both these disorders are associated with proximal myopathy and fra-
gility fractures, were ruled out. Proximal myopathy, fragility fracture, hypokalemia,
normal anion gap metabolic acidosis with failure to acidify urine (urine pH >5.5),
hypercalciuria, and radiological evidence of osteomalacia establishes the diagno-
sis of distal RTA. Diagnosis of RTA should be suspected in a patient who presents
with periodic paralysis, proximal myopathy, bony pains and deformities, and
nephrolithiasis/nephrocalcinosis. Biochemically, it can be confirmed by the pres-
ence of normal anion gap metabolic acidosis. Further, the estimation of urine pH
helps in differentiating between proximal and distal RTA, as proximal RTA is
associated with urine pH <5.5, whereas distal RTA >5.5. As the index patient had
urine pH of 6.5 in presence of normal anion gap metabolic acidosis, it suggests the
diagnosis of distal RTA. However, in milder/incomplete forms of distal RTA,
blood pH may be in a normal range due to compensation; therefore, ammonium
chloride loading test is recommended to establish the diagnosis of distal RTA in
such scenario. Hypokalemia, hypercalciuria, and hypocitraturia are the additional
evidences of the distal renal tubular dysfunction, whereas, aminoaciduria,
5 Rickets–Osteomalacia