INTRODUCTION — Osteomalacia is a disorder of decreased or defective mineralization of newly formed osteoid at sites of bone turnover, whereas rickets is a disorder of defective mineralization of cartilage in the epiphyseal growth plates of children. Osteomalacia and rickets can occur together in children (open growth plates), but only osteomalacia occurs in adults (fused growth plates). Several different disorders cause osteomalacia via mechanisms that result in hypocalcemia, hypophosphatemia, or direct inhibition of the mineralization process.
This topic will review the epidemiology, pathogenesis, and different causes of osteomalacia. The clinical manifestations, diagnosis, and treatment of osteomalacia and the etiology and treatment of rickets are discussed separately. (See "Clinical manifestations, diagnosis, and treatment of osteomalacia in adults" and "Etiology and treatment of calcipenic rickets in children".)
EPIDEMIOLOGY — There is a growing prevalence of vitamin D deficiency in many countries [1-4]. Severe and prolonged vitamin D deficiency (25-hydroxyvitamin D <10 ng/mL [25 nmol/L]) can result in hypocalcemia, secondary hyperparathyroidism, secondary hypophosphatemia, and osteomalacia [5]. Nutritional vitamin D deficiency is therefore an increasingly common cause of osteomalacia in adults. Populations at risk include homebound older adults who have little sun exposure and insufficient dietary calcium and vitamin D, patients with malabsorption (eg, related to gastrointestinal bypass surgery, inflammatory bowel disease, or celiac disease), and those with limited sun exposure due to clothing that covers most of the body or restrictions related to skin conditions [6-10]. Hereditary forms of vitamin D deficiency and resistance, which are identified in childhood, are also associated with osteomalacia in adults, but these disorders are less common.
Osteomalacia can also occur in patients with primary hypophosphatemia due to one of the hereditary hypophosphatemic rickets syndromes (eg, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets); these rare syndromes usually present in childhood but persist in adulthood. Hypophosphatemic osteomalacia presenting in adulthood may be due to tumor-induced osteomalacia, an acquired paraneoplastic syndrome of renal phosphate wasting. Drug-induced Fanconi syndrome can also result in renal phosphate wasting and osteomalacia. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)
PATHOGENESIS — Bone remodeling occurs continually on both trabecular and Haversian (cortical) bone surfaces. At any given time, approximately 7 percent of the bone surface is in the process of forming new bone. The osteoclast begins the cycle by excavating a cavity on the bone surface followed by refilling of the cavity by activated osteoblasts. New bone formation takes place in two steps:
●Osteoblasts lay down organic matrix, or osteoid (picture 1).
●The matrix then undergoes a process of maturation, which requires the synthesis of a number of enzymes over a period of approximately 10 to 15 days [11]. At this point, bone mineral is deposited as amorphous calcium phosphate that undergoes conversion to hydroxyapatite. The calcium is taken up by mitochondria from the extracellular space and transported to matrix vesicles. The phosphate is made available by alkaline phosphatase present in the matrix vesicles.
The rates of bone formation and calcification can be measured by histomorphometric techniques using double tetracycline labeling [12]. Tetracyclines are deposited as a band at the mineralization front and these bands can be visualized under a fluorescence microscope. After two courses of the antibiotic, separated by a period of days, the growth rate of the skeleton can be estimated in iliac crest biopsies by measurement of the distance between the bands of deposited tetracycline.
Two changes occur in osteomalacia (picture 2) [13]:
●The distance between tetracycline bands is reduced.
●The unmineralized matrix appears as a widened osteoid seam (more than 15 microns) and the osteoid volume is more than 10 percent [14].
Both features are necessary for the diagnosis of osteomalacia because other disorders may show one of these findings [13]. (See "Clinical manifestations, diagnosis, and treatment of osteomalacia in adults".)
Defective mineralization in osteomalacia is due to a lack of one or more of these necessary factors (table 1) [13]:
●Newly formed osteoid that is normal qualitatively and quantitatively. Fibrogenesis imperfecta ossium, osteogenesis imperfecta, and axial osteomalacia are examples of defective bone matrix formation and failure of mineralization despite normal plasma levels of calcium and phosphate.
●Normal concentrations of calcium and phosphate in extracellular fluid to allow uptake of calcium and phosphate. Hypophosphatemia, due to vitamin D deficiency and secondary hyperparathyroidism or primary renal tubular defects with phosphate wasting, is a common cause of osteomalacia. (See "Hypophosphatemia: Causes of hypophosphatemia".)
●Normal pH at the site of calcification. Chronic metabolic acidosis, as occurs in renal tubular acidosis, can affect mineralization.
●Adequate bioactivity of alkaline phosphatase. Hypophosphatasia is a rare disease characterized by low alkaline phosphatase levels, which results in accumulation of pyrophosphate, an inhibitor of mineralization.
●Absence of significant exposure to inhibitors of calcification, such as older bisphosphonates (eg, etidronate), aluminum, and, occasionally, high doses of fluorides. (See "Pharmacology of bisphosphonates", section on 'Mineralization'.)
ETIOLOGY — Several different disorders cause osteomalacia via mechanisms that result in hypocalcemia, hypophosphatemia, or direct inhibition of the mineralization process (table 1).
Vitamin D deficiency and resistance — Vitamin D deficiency or resistance may result in osteomalacia by one of four mechanisms [15]:
●Impaired availability of vitamin D, secondary to inadequate dietary vitamin D, fat malabsorptive disorders, and/or lack of photoisomerization
●Impaired 25-hydroxylation of vitamin D in the liver to 25-hydroxyvitamin D (eg, due to severe liver disease)
●Impaired 1 alpha-hydroxylation of 25-hydroxyvitamin D in the kidney to 1,25-dihydroxyvitamin D
●End-organ insensitivity to vitamin D metabolites (hereditary vitamin D-resistant rickets)
The most common cause of osteomalacia worldwide is dietary vitamin D deficiency combined with lack of sun exposure and, in the United States, gastrointestinal disease or postsurgical states with altered intestinal absorption. Causes of vitamin D deficiency are reviewed separately. (See "Causes of vitamin D deficiency and resistance" and "Etiology and treatment of calcipenic rickets in children".)
Inadequate calcium intake — Inadequate intake of calcium may contribute to the development of osteomalacia [1,16]. Among African children with rickets in whom exposure to sunlight was adequate, the intake of calcium (with or without vitamin D supplementation) was superior to vitamin D alone in improving the biochemical and radiographic manifestations of rickets [17]. Although the exact cause of rickets in these children was unclear, sufficient ingestion of calcium as well as vitamin D in childhood appears essential for adequate skeletal formation. (See "Etiology and treatment of calcipenic rickets in children", section on 'Calcium deficiency'.)
Hypophosphatemia — In disorders of vitamin D metabolism, hypophosphatemia can be an important contributor to osteomalacia. In these settings, secondary hyperparathyroidism can lead to urinary phosphate wasting. Disorders that cause calcitriol deficiency also result in impaired intestinal absorption of phosphate as well as calcium. (See "Causes of vitamin D deficiency and resistance", section on 'Vitamin D-dependent rickets type IA (VDDR-1A)'.)
Primary renal phosphate wasting syndromes can be inherited or acquired, either as an idiopathic disorder or in association with mesenchymal tumors (tumor-induced osteomalacia) [18] (see "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia"). The use of parental polymaltose-containing iron infusions has also been reported to cause hypophosphatemia-associated osteomalacia [19]. These disorders result from excessive circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23), or other phosphaturic proteins (sometimes referred to collectively as "phosphatonins").
Renal phosphate wasting can also occur as part of an overall defect in proximal tubular transport in Fanconi syndrome. In adults, Fanconi syndrome is commonly caused by multiple myeloma, which is often latent [20]. It has also been reported in the context of exposure to several medications, including antivirals (tenofovir, adefovir), aminoglycoside antibiotics, sodium valproate, and fumaric acid esters [21-26], and after exposure to heavy metals, such as cadmium. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA' and "Epidemiology and toxicity of cadmium", section on 'Kidney disease'.)
Chronic kidney disease — Bone disease in chronic kidney disease is due to a number of factors, including reduced formation of 1,25-dihydroxyvitamin D (calcitriol), metabolic acidosis, and administration of aluminum. Historically, aluminum-containing antacids were the predominant cause of osteomalacia in this setting but are now much less commonly used because other, safer phosphate binders are now commonly available. (See "Management of hyperphosphatemia in adults with chronic kidney disease" and "Aluminum toxicity in chronic kidney disease".)
Renal tubular acidosis — Osteomalacia or rickets is most often seen with proximal (type 2) renal tubular acidosis/Fanconi syndrome [27]. In this setting, proximal phosphate wasting, metabolic acidosis, and secondary hyperparathyroidism may all contribute to the decrease in bone mineralization. Metabolic acidosis can both promote calcium loss and directly impair mineralization. (See 'Pathogenesis' above.)
Although the association is controversial, osteomalacia has also been reported in patients with distal (type 1) renal tubular acidosis [28-30]. In one study, for example, two of seven patients with Sjögren's disease and distal renal tubular acidosis also had findings consistent with osteomalacia [28]. Osteopenia and decreased bone formation have been described in this setting, with correction of acidosis increasing the bone formation rate [28]. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis".)
Mineralization inhibitors — Osteomalacia is occasionally due to mineralization inhibitors. Included in this group are:
●Bisphosphonates, which have a structure similar to native pyrophosphate, an important inhibitor of mineralization [31]. Continuous use of etidronate, a non-nitrogenous bisphosphonate, has been associated with mineralization defects. However, there are differences among the bisphosphonates in their potential to inhibit mineralization and cause osteomalacia. The circulating concentrations of the nitrogen-containing bisphosphonates currently in use (eg, alendronate, risedronate, ibandronate, and zoledronic acid) do not cause osteomalacia. (See "Pharmacology of bisphosphonates", section on 'Mineralization'.)
●Aluminum, which has been implicated in osteomalacia in patients with chronic kidney disease as well as in those receiving total parenteral nutrition and amino acids in the form of casein hydrolysate [32,33].
●Fluoride, which can cause osteomalacia when ingested in excessive quantities, as may occur in endemic fluorosis [34] and with ingestion of fluoride toothpastes and certain teas [35].
Hypophosphatasia — Hypophosphatasia is a rare, genetic disease, characterized by mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene, leading to a diminished activity of the TNSALP enzyme in target tissues and accumulation of TNSALP substrates, including inorganic pyrophosphate, an inhibitor of mineralization [36,37]. Clinical features include low levels of alkaline phosphatase in serum and bone and the development of osteomalacia and periodontal disease. Owing to the large number of described mutations in the TNSALP gene and variable clinical expression, there is a very wide range of disease severity ranging from lethal perinatal forms to milder fracture phenotypes that present in adulthood or isolated dental manifestations (premature loss of deciduous teeth and/or extensive dental caries).
●In infancy and childhood, features of hypophosphatasia [37] may include hypotonia, respiratory compromise, rachitic deformities, delayed walking and gait abnormalities, craniosynostosis, recurrent fractures, bone pain and short stature, premature loss of deciduous teeth, and seizures.
The availability of enzyme replacement therapy with asfotase alfa (recombinant tissue-nonspecific isoenzyme of alkaline phosphatase [TNSALP]) for the treatment of childhood-onset hypophosphatasia has altered the natural history of this condition [38]. (See "Clinical manifestations, diagnosis, and treatment of osteomalacia in adults", section on 'Other causes'.)
●In adulthood, hypophosphatasia is most commonly characterized by the presence of poorly healing, recurrent fractures (commonly affecting the extremities), and bone pain (thighs and hips), as well as an increased incidence of pyrophosphate arthropathy and chondrocalcinosis [37,39-41].
In adolescents and adults with hypophosphatasia, asfotase alfa may improve motor function [42].
Defective bone matrix — Axial osteomalacia is a rare, generalized skeletal disorder of defective bone mineralization that presents with chronic axial skeletal pain, most often in the cervical spine [43]. Men are affected more often than women, and it may be familial. Radiographic abnormalities (coarsened trabecular pattern) are seen in the spine and pelvis. Histopathologic studies of bone reveal osteoidosis and failure of tetracycline deposition. The pathogenesis is uncertain, but genetic etiologies and an association with sacroiliitis have been suggested [44,45].
Fibrogenesis imperfecta ossium is a very rare, progressive, idiopathic disorder of defective bone matrix formation and impaired mineralization [46,47]. Symptoms begin in adult life with pain, fractures, and weakness. Serum alkaline phosphatase may be elevated, consistent with a mineralization defect. It affects the entire skeleton and is characterized pathologically by the absence of normal birefringent collagen fibrils. Some cases have been associated with a monoclonal or polyclonal gammopathy. The cause is unknown.
SUMMARY
●Pathogenesis – Osteomalacia is a disorder of defective mineralization of newly formed osteoid at sites of bone turnover. (See 'Introduction' above.)
Mineralization abnormalities occur as a consequence of inadequate calcium, phosphate, vitamin D, and/or alkaline phosphatase levels, or in the presence of abnormal bone matrix or direct inhibition of the mineralization process. (See 'Pathogenesis' above.)
●Etiology – Several different disorders cause osteomalacia. Severe vitamin D deficiency (25-hydroxyvitamin D <10 ng/dL [25 nmol/L]), secondary to inadequate dietary intake, lack of sun exposure, or conditions leading to gastrointestinal malabsorption, is the most common cause of osteomalacia in adults. (See 'Etiology' above and "Causes of vitamin D deficiency and resistance".)
Other causes include hereditary or acquired disorders of phosphate wasting, type 2 renal tubular acidosis, and excessive exposure to inhibitors of bone mineralization (eg, aluminum toxicity, endemic fluorosis) (table 1). (See 'Etiology' above.)
Do you want to add Medilib to your home screen?