Osteomalacia and rickets are terms that describe the clinical, histologic, and radiologic abnormalities of bone that are associated with more than 50 diseases and conditions. Osteomalacia is a disorder of mature (adult) bone, whereas rickets occurs in growing bone. Although rickets and osteomalacia were initially viewed as distinct clinical entities, the same pathologic processes may result in either disorder. In both conditions, mineralization of newly formed osteoid (the bone protein matrix) is inadequate or delayed. In individuals with rickets, defective mineralization occurs in both bones and cartilage of the epiphyseal growth plates and is associated with growth retardation and skeletal deformities that are not typically seen in adults with osteomalacia.

In the United States at the beginning of the 20th century, rickets due to a deficiency of vitamin D was common in urban areas. In the 1920s, rickets was virtually eliminated by an appreciation of the antirachitic properties of sunlight and the use of cod liver oil (which contains vitamin D). However, with the development of effective treatments for previously fatal diseases that affect vitamin D metabolism (such as chronic renal failure) and with an improved understanding of both vitamin D and mineral metabolism, many additional syndromes with osteomalacia or rickets as a feature have emerged. Many later studies have demonstrated that undiagnosed vitamin D deficiency or insufficiency is common in the United States, and for a significant number of adult women with osteoporosis, vitamin D insufficiency may be an unsuspected component of their bone loss.

The primary abnormality of bone in patients with either osteomalacia or rickets is defective mineralization of the bone matrix. The major mineral in bone is hydroxyapatite—Ca₁₀(PO₄)₆(OH)₂. Thus, any disease that results in decreased availability to bone of either calcium or phosphorus may result in osteomalacia or rickets (Table 11-1). Causes of osteomalacia and rickets fall into three categories: (1) disorders associated with abnormalities of vitamin D metabolism or action that limit the availability of calcium for mineralization of bone, (2) disorders associated with abnormalities of phosphorus metabolism, and (3) a small group of disorders in which there is normal vitamin D and mineral metabolism.

Serum vitamin D comes from two sources: dietary intake and conversion by ultraviolet (UV) irradiation of 7-dehydrocholesterol or ergosterol in the skin. Vitamin D is then transported through the blood to the liver, where it is converted to 25-hydroxyvitamin D (25-OHD) by the hepatic 25-hydroxylase enzyme. The 25-OHD is then converted in the kidney to the active hormone, 1,25-dihydroxyvitamin D, by the renal 1α-hydroxylase enzyme. This active vitamin D metabolite has effects in many tissues, including the intestine (increases calcium absorption), the kidney (increases calcium reabsorption), the parathyroid glands (decreases parathyroid hormone [PTH] secretion), and bone (stimulates osteoblast maturation and bone matrix synthesis) (Fig. 11-1). Studies have now suggested possible other roles for vitamin D in cardiovascular and neurologic diseases, insulin resistance and diabetes, malignancies, autoimmune conditions, and infections. From an understanding of how vitamin D is metabolized, it is apparent that even when dietary intake and UV-mediated vitamin D synthesis are normal, vitamin D deficiency may occur in association with severe malabsorptive, renal, or liver disease.

Clinically apparent vitamin D deficiency is rarely seen in the United States except when exposure to sunlight and intake of vitamin D–fortified milk and other dairy products are limited. However, many elderly Americans are at risk for occult vitamin D deficiency or insufficiency because of sun avoidance, sunscreen use, an age-related decrease in dermal vitamin D synthesis, impaired hepatic and renal vitamin D hydroxylation, and diminished intestinal responsiveness to 1,25-dihydroxyvitamin D. Celiac disease or sprue, regional enteritis, intestinal bypass surgery, partial gastrectomy, chronic liver disease, primary biliary cirrhosis, pancreatic insufficiency, chronic renal failure, and certain medications have also been associated with the development of osteomalacia.

Two extremely rare genetic syndromes are also associated with rickets. Vitamin D–dependent rickets (VDDR) type I (also called pseudovitamin D deficiency rickets) is caused by an almost complete absence of renal 25-hydroxyvitamin D–1α-hydroxylase activity. VDDR type II results from a mutation of the vitamin D receptor gene that causes end-organ resistance to 1,25-dihydroxyvitamin D and lack of vitamin D action.

Nutritional phosphate deficiency, decreased intestinal phosphate absorption due to ingestion of phosphate binders (such as aluminum hydroxide), or renal phosphate wasting may result in osteomalacia or rickets. Hypophosphatemic rickets (also called vitamin D–resistant rickets) is a syndrome of renal phosphate wasting and decreased renal synthesis of 1,25-dihydroxyvitamin D. Hypophosphatemic rickets, which is transmitted as an X-linked dominant trait, is the most common inherited form of rickets. Another syndrome, tumor-induced osteomalacia, is observed when usually benign neoplasms of mesenchymal origin secrete fibroblast growth factor-23 (FGF-23), which promotes renal phosphate wasting and produces osteomalacia.