Aetiology
Vitamin D deficiency is the primary cause of osteomalacia in the Western world, resulting from inadequate endogenous production of vitamin D3 in the skin related to:
Suboptimal UV-B sunlight exposure and the use of sunscreen
Insufficient dietary supplementation, and/or
The inability of the small intestine to absorb adequate amounts of dietary sources of vitamin D
Data from randomised controlled trials have shown that UVB exposure is the major contributor to changes in 25-hydroxyvitamin D levels in the UK.[17] Resistance to the effects of vitamin D can result from the use of drugs that antagonise vitamin D action or cause alterations in vitamin D metabolism.[18] Malabsorption of vitamin D and calcium is a major cause of osteomalacia in the US, with gastrectomy and coeliac disease accounting for up to 66% of all cases of osteomalacia. Osteomalacia occurs in up to 33% of patients after a gastrectomy.[19] Malabsorption of vitamin D and calcium related to bariatric procedures for weight loss is emerging as a common cause of vitamin D deficiency and consequently osteomalacia.[20][21][22][23]
Chronic kidney disease-mineral bone disorder (CKD-MBD) is a global term applied to all pathological features of bone in patients with chronic renal failure. Clinical symptoms of bone disease are present in fewer than 10% of patients with end-stage renal disease; however, x-ray abnormalities are observed in about 35% cases, and histological abnormalities are observed in about 90% cases.[24]
Hypophosphataemia, related to increased urinary phosphate excretion, is an important cause of inherited and acquired forms of osteomalacia. Acquired mesenchymal tumours can cause a tumour-induced osteomalacia with phosphate wasting secondary to a phosphatonin, FGF-23.[25] Hypophosphataemia is also a feature of X-linked hypophosphataemic rickets, autosomal dominant and recessive rickets, alcohol abuse, poorly controlled diabetes, metabolic acidosis, and diuretic use.
Osteomalacia may be a feature of proximal (type 2) renal tubular acidosis and inherited and acquired forms of Fanconi's syndrome.[26] Bone mineralisation may be inhibited by the first-generation bisphosphonates, aluminium-containing phosphate binders, prolonged total parenteral nutrition, or dietary luoride.[3][27][28]
Inborn errors of metabolism characterised by under-active tissue-non-specific isoenzyme of alkaline phosphatase in the serum and bone are associated with the development of osteomalacia and severe periodontal disease.[4] There are multiple modes of inheritance of hypophosphatasia and a variable spectrum of disease manifestations. Diagnosis is based on elevated levels of phosphoethanolamine and pyrophosphates in the blood and urine. Patients with cystic fibrosis have a high prevalence of low bone mass (including osteomalacia), related in part to malnutrition, with vitamin D and calcium deficiencies leading to a high incidence of fractures.[29]
Pathophysiology
Osteomalacia results from defective bone mineralisation. This is a result of a lack of one or more of the factors necessary for osteogenesis, namely, a normal extracellular concentration of calcium and phosphate and a normal pH at the site of calcification.[30] Normal mineralisation depends on interdependent factors that supply adequate calcium and phosphate to the bones. Vitamin D maintains calcium and phosphate homeostasis through its actions on the GI tract, the kidneys, the bone, and the parathyroid glands. Vitamin D is obtained from the diet, or it can be produced from a sterol precursor (7-dehydrocholesterol) in the skin following exposure to UV-B light.
Sequential hydroxylation of vitamin D is required to produce the metabolically active form of vitamin D. Hydroxylation occurs first in the liver and then in the kidneys and produces 1,25-dihydroxyvitamin D. Dysfunction in any of these metabolic steps results in osteomalacia and secondary hyperparathyroidism in adults.
The active metabolite of 1,25-dihydroxyvitamin D is essential for maintaining normocalcaemia through ensuring adequate intestinal calcium absorption. Inadequate intestinal calcium absorption leads to a fall in blood ionised calcium and secondary hyperparathyroidism. Low 1,25-dihydroxyvitamin D levels may contribute to secondary hyperparathyroidism through a reduction in the suppressive effects of 1,25-dihydroxyvitamin D on PTH gene transcription. PTH decreases urinary calcium excretion and increases renal tubular phosphate loss. Therefore, serum phosphate levels are reduced, despite an increase in phosphate release from bone. Osteopenia results from increased bone resorption, occurring through an indirect effect of PTH, which increases both osteoclast numbers and activity.
A number of drugs interfere with the normal metabolism of vitamin D to 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, leading to alterations in calcium homeostasis. Rickets or osteomalacia may result from the increased catabolism of vitamin D and its metabolites via the induction of hepatic cytochrome P450 enzymes.
Hyperphosphataemia in chronic kidney disease-mineral bone disorder (CKD-MBD) directly induces hypocalcaemia and decreases the efficacy of 1-alpha-hydroxylase in the kidney. This, in turn, decreases active vitamin D metabolites and thus the ability of the gut to absorb calcium. Subsequently, secondary hyperparathyroidism develops.
Classification
Acquired or inherited aetiologies
Nutritional deficiencies: vitamin D, phosphorus, and calcium deficiency related to dietary deficiency, malabsorption, or lack of UV-B light exposure
Drug-induced: anticonvulsants increase the catabolism of vitamin D and reduce intestinal calcium absorption.
Renal osteodystrophy (currently known as chronic kidney disease-mineral bone disorder [CKD-MBD]): combines features of secondary hyperparathyroidism, rickets, osteomalacia, and osteoporosis
Mineralisation inhibitors: first-generation bisphosphonates and fluoride toxicity.
Tumour-induced: an acquired paraneoplastic syndrome of renal phosphate wasting that resembles genetic forms of hypophosphataemic rickets.
Inherited:[4]
Vitamin D-dependent rickets (types 1 and 2; calciopenic rickets)
Hypophosphatasia: inborn error of metabolism characterised by subnormal activity of tissue-non-specific (bone/liver/kidney) isoenzymes of alkaline phosphatase and associated with the development of osteomalacia and severe periodontal disease.
Hypophosphataemic rickets: X-linked hypophosphataemic rickets (most common form of hereditary rickets), autosomal dominant hypophosphataemic rickets (ADHR), autosomal recessive hypophosphataemic rickets (ARHR), and hypophosphataemic rickets with hypercalciuria (HHRH).
Fanconi's syndrome and renal tubular acidosis: decreased reabsorption of phosphorus, glucose, and amino acids in the proximal tubules, accompanied by bicarbonate wasting (type 2 renal tubular acidosis). Tenofovir, a commonly used antiretroviral for HIV treatment, can cause Fanconi's syndrome. Valproate-induced Fanconi's syndrome has also been described.
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