Vitamin-D, calcium, and phosphorus are the main factors that influence bone maturation and mineralization. Defective mineralization can lead to rickets and/or osteomalacia. Rickets is characterized by a defect in mineralization and the widening of the epiphyseal plates. Osteomalacia, however, is a defect in the mineralization of the bone matrix. Both rickets and osteomalacia usually occur together in children. Rickets occurs exclusively in children, whereas adults develop osteomalacia after the epiphyseal plate fusion. Whistler, Boate, Glisson, and their colleagues, Fellows of the Royal College of Physicians, London, in the seventeenth century, were the first to describe rickets in the medical literature. Nutritional rickets is the most common cause of bone disease all over the world.
Vitamin D deficiency is, by far, the most common cause of nutritional rickets. Rarely, nutritional deficiency of calcium or phosphorus can result in rickets. Other less frequent causes of rickets include genetic causes, drug-induced rickets, and rickets secondary to liver diseases. Medications that impair vitamin D metabolisms such as diphenylhydantoin and rifampicin can result in rickets.
Based on the biochemical profile, rickets can be classified into calcipenic, phosphopenic, and rickets due to inhibited mineralization.
Vitamin D-dependent rickets: This group is characterized by defects in either synthesis of the active form of vitamin D (1,25-dihydroxy vitamin D), or defect in vitamin D receptor (VDR), or vitamin D-VDR interactions.
Congenital hypophosphatemic rickets: In this type, the defect in bone mineralization is caused by hypophosphatemia (secondary to renal phosphate loss). It is classified into two groups, FGF-23-dependent hypophosphatemic rickets, and FGF-23-independent hypophosphatemic rickets.
The main causes of rickets worldwide in older infants and toddlers are due to vitamin D deficiency, either due to nutritional deficiency or due to insufficient sun exposure. A study revealed 89% of the patients with rickets had no or minimal sun exposure. Risk factors for nutritional vitamin D deficiency include prolonged exclusive breastfeeding without vitamin D supplementation, excessive juice rather than fortified milk consumption, and inadequate intake of vitamin D fortified foods. Pregnant mothers who have a vitamin D deficiency may predispose their babies to rickets and hypocalcemia. Latitude also plays an important role in vitamin D deficiency and rickets. In higher latitudes, there are more chances to develop vitamin D deficiency and rickets. This happens because latitude affects the zenith angle of the sun, and subsequently, the amount of the ultraviolet B (UVB) radiation. Even in the countries where the sunlight is available throughout the year, limited sun exposure can occur due to the following reasons - clothing that covers most of the skin (due to religious, or cultural, or climatic reasons), being indoors for most of the time, having dark skin color (high concentrations of melanin in the skin reduce vitamin D synthesis) or reduced dietary intake (vegetarians), living in a region with high atmospheric pollution (pollutions limit the UVB rays from reaching the ground levels), or extensive use of sunscreens with protection factor > 8. The safe threshold for UVB exposure for vitamin D synthesis without an increased risk for skin cancer is unknown.
The prevalence of the disease has increased in both developed and developing countries. Yet, generally speaking, the prevalence of rickets is higher in developing counties than in developed countries. African, Middle Eastern, and Asian countries have a wide prevalence rate of 10% to 70%. Historically, the prevalence of rickets in the developed countries significantly decreased following the widespread introduction of dietary vitamin D supplementation, legislation to improve air quality, and recognition of the importance of vitamin D and bone health by the public. In the U.S., vitamin D milk fortification (100 IU/cup) was started in the 1930s.
The worldwide incidence has been estimated differently per 100,000 in various countries as follows: in Canada, 2.9; in New Zealand, 10.5 among children less than three years while it is 2.2 in the older age group (3-15 years); in Australia, 4.9; in Turkey, 3.8; and in the United Kingdom, 7.5. In the U.S., specifically in Minnesota, there is a substantial increase in the incidence in the last 20 years. The reported incidences in the 1970s, 1980s, 1990s, and 2000s were 0, 2.2, 3.7, and 24.1, respectively. Restricted sunlight (UVB) exposure is one of the reasons for this increasing prevalence. Native Alaskan children are at considerable risk for developing rickets than other U.S. populations. The incidence of the rickets hospitalization rate is the highest in Alaska among all U.S. regions, 2.23/100,000 versus 1.23/ 100,000. The incidence of rickets in Alaska is significantly high because of higher latitudes.
The osseous tissue in the growing long bones is created from the cartilage by a process called endochondral ossification. The chondrocytes in the cartilage grow to form the hypertrophic chondrocytes, which then start producing the cartilage matrix. This cartilage matrix is then calcified, which is reabsorbed and replaced with woven bone, which is later replaced by mature lamellar bone. In these processes, there is a formation of unmineralized bone tissue (osteoid), and the osteoid is mineralized in the presence of adequate calcium and phosphate levels. Any defect in osteoid mineralization may cause rickets. In all types of rickets, the characteristic features occur at the growth plate.
Calcium and phosphorus are required for the normal matrix mineralization. Reduction in these minerals causes abnormal mineralization. Normal serum calcium levels require sufficient dietary calcium intake, normal calcium absorption through the gastrointestinal tract, and adequate active form of vitamin D.
Vitamin D levels are maintained either by endogenous synthesis or dietary intake.
Low serum calcium, either from its low intake or from vitamin D deficiency, causes a compensatory increase in the PTH, which subsequently causes hypophosphatemia. Low serum phosphate, in turn, inhibits the apoptosis of chondrocytes and thereby accumulation of hypertrophic chondrocytes. Eventually, abnormal growth of the cartilaginous epiphyseal plate occurs. This results in many of the clinical manifestations as well as the radiological changes (widening of epiphysis) of rickets. Growth plate abnormalities occur due to reduced vascular invasion with decreased chondroblast and osteoclast activity.
A detailed history and a thorough physical examination are essential to diagnose patients with rickets. History should include the gestational age of the child, details of sunlight exposure, dietary history including intake of supplements, developmental/growth history, and pertinent family history. Positive family history of skeletal abnormalities, stunted growth, alopecia, dental abnormalities, parental consanguinity may suggest a genetic cause of rickets. Physical examinations should include detailed skeletal examination (with attention to any tenderness, deformities, softening, asymmetry, and neurological abnormalities) as well as a detailed dental evaluation. History and physical examination usually give clues to diagnose rickets. However, the absence of clinical signs of rickets doesn’t exclude this diagnosis, especially in the early stages.
The clinical manifestations of rickets are variable based on the underlying etiology, severity, and duration of the disease. Rickets is frequently noted in children between 6 months to 2 years of life. Children frequently have some osseous clinical manifestations (often noted at the sites of rapid bone proliferation):
Other manifestations of rickets are as follows:
If the rickets is clinically suspected, biochemical tests and radiological images are the next steps to confirm the diagnosis.
The most important laboratory marker to diagnose the rickets is serum alkaline phosphatase (ALP), which is typically high as this is a disease of abnormal mineralization and increased osteoblastic activity. Alkaline phosphatase activity is induced by phosphate deficiency in rickets. In phosphopenic rickets, ALP values are frequently noted between 400-800 IU/L, and in calcipenic rickets, ALP is markedly elevated, and values are frequently noted up to/greater than 2000 IU/L. It is also an excellent marker to monitor disease activity.
Serum 25-hydroxyvitamin D level is another laboratory marker that helps to diagnose rickets, especially the nutritional deficiency of vitamin D. The active form of vitamin D (1,25-dihydroxy vitamin D) has a short half-life (5-10 hours). Serum 25-hydroxyvitamin D level is the major circulatory form and is typically used to assess vitamin D status. The majority of children with vitamin D deficiency-induced nutritional rickets have serum 25 hydroxyvitamin D level < 10 ng/mL. (The global consensus recommendations on the prevention and treatment of nutritional rickets defined vitamin D deficiency as 25-hydroxyvitamin D level < 30 ng/mL, insufficiency as 30 to 50 ng/mL, and an adequate level as >50 ng/mL.
Routine screening with serum 25 hydroxyvitamin D levels is not recommended for healthy children. Serum 1,25 dihydroxy vitamin D levels are helpful in the evaluation of genetic forms of vitamin D dependent rickets. Generally, 1,25-dihydroxy vitamin D levels are low in vitamin D-dependent rickets type I (A and B) and high in vitamin D-dependent rickets type II (A and B).
Serum calcium and phosphate levels could vary depending on the type of rickets - calcipenic or phosphopenic type. Serum calcium and PTH levels are usually normal in phosphopenic type. In calcipenic rickets, serum calcium levels are either low or normal (as a result of compensatory increases in PTH). If the serum albumin is low, serum calcium levels should be corrected accordingly. In calcipenic rickets, the serum phosphate level is initially normal but drops later in the disease due to renal phosphate loss as a result of elevated PTH.
Measuring urine phosphate is helpful in evaluating the renal loss of phosphate in the genetic forms of hypophosphatemic rickets and other conditions such as Fanconi syndrome associated with phosphaturia. Similarly, urine calcium can be used to monitor hypercalciuria (to prevent nephrocalcinosis) during the treatment phase of hypocalcemic rickets.
Other biochemical investigations include blood urea nitrogen (BUN)/creatinine levels to screen for renal status, and liver enzymes to screen liver function.
The radiological images should include the distal ends of rapidly growing bones in upper and lower extremities, and additionally, ribcage images are helpful as well. The appearance of radiolucent lines at the conjunction between epiphysis and metaphysis and widening of the epiphyseal plate, due to the accumulation of non-mineralized osteoid, is the earliest radiological change. Rachitic changes also include the cupping, splaying, fraying, and trabecular formation of the metaphysis. The epiphyseal center formation may be delayed or appear small. The cortex of the bones may be thin and osteopenic. Chest images show rachitic rosary and widening of costochondral junctions. Angular deformities, along with pathological fractures of the upper and lower limb bones, may be noted in advanced stages.
The combination of positive clinical signs, relevant laboratory findings (high ALP, and either hypocalcemia or hypophosphatemia), and typical radiological findings confirm the diagnosis of rickets. The diagnosis is still possible in the presence of normal serum calcium and phosphate levels. Similarly, clinical signs are not recognized in the early stages.
Treatment strategies of rickets depend on the underlying etiology - nutritional vs. genetic rickets.
Treatment of rickets due to nutritional deficiency of vitamin D:
Treatment includes early intensive and late maintenance phase. There are several regimens utilized to treat rickets due to nutritional deficiency of vitamin D. All of them comprise some form of vitamin D administration, vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol), with subsequent monitoring for healing. The intensive phase of vitamin D treatment is given for two to three months in conjunction with calcium supplementation (500 mg either through diet or by supplements) for children who have insufficient dietary calcium.
In toddlers, bone pain improves within two weeks after treatment initiation. The metaphyseal swelling improves by six months, and the bow legs and knock knee improvement can take up to 2 years. However, adolescents are usually left with some residuals that may need orthopedic surgical correction.
Biochemically, serum calcium, and phosphate levels return to normal levels within six to ten days, whereas PTH normalizes in one to two months. ALP may normalize in three months or longer.
Once the treatment is started, careful monitoring of serum calcium, phosphate, ALP, and 25 hydroxyvitamin D is carried out. Random urine calcium to creatinine ratio should be measured to evaluate any increase in urinary calcium, which is often used to monitor the need to adjust the treatment and also to evaluate for hypercalciuria to prevent nephrocalcinosis. After treatment of the biochemical abnormalities and vitamin D restoration, severe persistent osseous abnormalities may be treated surgically.
Prevention of rickets due to nutritional deficiency of vitamin D: This is a preventable disease. The optimal way to prevent nutritional rickets is to educate the parents and pregnant women about the good dietary sources of calcium and vitamin D as well as about the importance of adequate sun exposure. However, the safe threshold limit for sunlight exposure for vitamin D synthesis without an increased risk for skin cancer is not known. The pregnant women ideally should receive 600 IU per day of vitamin D in combination with other micronutrients to prevent rickets in their offsprings. Vitamin D supplementation during pregnancy helps to avoid high levels of placental ALP and subsequent increase in the neonatal fontanel size, hypocalcemia, and dental enamel complications.
Additionally, rickets can be prevented by a universal oral vitamin D supplementation of 400 IU given daily to breastfed infants and infants who consume less than 500 mL of fortified formula per day in the first year of their life. Beyond infancy, the high-risk groups for vitamin D deficiency (children with a previous history of rickets, and high risk of insufficient dietary vitamin D) should receive 600 IU of vitamin D daily either by diet or by supplementation.
Vitamin D supplementation is an effective intervention in preventing vitamin D deficiency rickets. For example, a nationwide program in turkey was introduced in 2005 to propose a free vitamin D drops (400 IU/day) to children less than three years. The prevalence of rickets has dropped from 6% in 1998 to 0.1% in 2008. The residents of the geographical areas located higher than 55th attitudes in Canada were recommended taking higher daily maintenance doses of 800 IU through dietary sources and/or vitamin D supplementation.
Treatments of rickets due to genetic causes:
Rickets should be differentiated from the following conditions that mimic based on either the biochemical abnormalities or radiological features:
The prognosis depends on the cause and severity of rickets. Nutritional rickets has a promising prognosis with prompt recognition and early institution of treatment. It can be cured completely within a few months from starting treatment. However, untreated patients may end with catastrophic complications. On the other hand, genetic causes of rickets mostly are not curable, and the treatment is symptomatic to improve the quality of life and management of complications.
The potential complication of the untreated condition includes poor linear growth, osseous deformities, multiple pathological fractures, hydrocephalus, increased intracranial hypertension (ICH), abnormal dentition (dental caries, dental hypoplasia, delayed dentition). Persistent hypocalcemia can lead to complications such as skeletal and cardiac myopathy, seizures, and eventual death.
The parents should be educated about good dietary sources for vitamin D and calcium, fortified food consumption, and also about adequate sun exposure. Vitamin D supplementation to pregnant women and infants is crucial to prevent this condition. Additionally, this condition would get a great benefit from governmental nutritional assistant programs such as the Supplemental Nutrition Assistance Program (SNAP) in addressing nutritional deficiencies.
Ideally, rickets is treated with a multidisciplinary approach. The treated team ideally should consist of a primary care physician (pediatrician), registered dietitian, and pediatric endocrinologist. Radiologists help in the interpretation of rachitic radiographic features from other conditions. Referral to an orthopedic surgeon may be needed to treat the deformities. Additionally, in genetic cases of rickets, referral to a geneticist in providing genetic counseling for the family. Consultation with a pediatric nephrologist and/or metabolic bone specialist is helpful in genetic conditions. The role of pharmacists is indispensable in helping clinicians in administering medications.) Other specialists, such as cardiologists, neurologists, physical therapists, and occupational therapists, help in the management of associated complications.
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