June 2007 | Back to Table of Contents
Commentary
Pediatric Bone Disease
A Decade of Discovery
By Philip R. Fischer M.D.*
Physicians should be aware that rickets is reappearing in the United States and that there’s new information about this old disease.
Many of the things we need can wait.
The child cannot.
Right now is the time his bones are being formed, his blood is
being made and his senses are being developed.
To him we cannot answer “Tomorrow.”
His name is “Today.”
—Nobel laureate Gabriela Mistral,
from “Su Nombre es Hoy”
During the 1990s, while working in Nigeria, family physician Tom D. Thacher, M.D., made a simple observation—that there seemed to be a lot of children with crooked legs. He wrote to me, asking if I could help explain why sun-exposed kids would so frequently have rickets. At that time, it was widely believed that vitamin D deficiency was the main cause of rickets.
That question stimulated an investigation. We garnered funding and delved into the issue, finding that many kids in central Nigeria, 5% to 10% in some communities, had curving deformities of the lower limbs.1 In addition to their leg abnormalities, affected children often had widened wrists and ankles, and beaded ribs. Radiographs of the distal wrists showed wide growth plates with fraying and cupping. These children didn’t have renal disease and weren’t taking medications, and they played outside. Clinically, it seemed that they had rickets, but vitamin D deficiency wouldn’t be expected in active 2- to 5-year-olds who played daily in the tropical sun.
During the course of our investigation, we determined that the affected children did indeed have rickets and normal vitamin D levels.2 But their calcium intake was less than 25 percent of the recommended daily amount. We wondered, could calcium deficiency be causing rickets?
Although the idea ran counter to the thinking of the time—for example, a 1996 editorial in the Journal of Pediatrics opined “We do not believe that calcium deficiency causes rickets in humans”3—we decided to pursue the question. We discovered that there had been a report suggesting that calcium insufficiency might be etiologically relevant in South Africa.4 Another suggested that in a therapeutic trial, rachitic children responded more favorably to treatment with calcium than to treatment with vitamin D.5 Calcium deficiency could indeed be responsible for rickets.6
A child’s growing body, however, is a complex creation, and a simple explanation didn’t fully answer all of our questions. We realized that the calcium intake of Nigerian children was uniformly low, yet only some of the children developed rickets.7 So we explored other factors that we thought might be relevant. Lead toxicity was common in Nigeria, with 70 percent of children having elevated levels of lead in their bloodstream. Yet this potentially competing divalent cation was not related to calcium deficiency or rickets.8,9 And there was no evidence that young children had vitamin D deficiency.1 Calcium absorption didn’t seem to vary between rachitic children and their nonrachitic peers.10 Instead, we began to realize that genetic factors are linked to rickets.11 A newly described mutation seems to explain the disease in a subset of patients.12 And interestingly, mothers of children with rickets produce less calcium in their breast milk than do mothers of children without rickets.13
In the span of a few short years, we had learned that rickets remained common in parts of the world and calcium deficiency, not just vitamin D deficiency, was an important cause of the disease.14 The next question we asked was Could anything be done about this?
Lesson from Bangladesh
We learned, surprisingly in Bangladesh, that the answer is an unequivocal yes. A nutritional biochemist had invited me to southeastern Bangladesh after noticing many children with rickets. Elders in villages explained that rickets had first been noted there about 15 years earlier, and no one knew why this “new” disease had emerged. I saw for myself the children with rickets and learned that they had normal vitamin D levels and low calcium intakes. We found no evidence of any environmental or toxic cause of the “new” disease.15
In 2006, I decided to return to Bangladesh. I invited Peter Tebben, M.D., to accompany me. At the time, Tebben was an endocrinology fellow at Mayo Clinic with an interest in rickets. He had seen U.S. children in renal failure with rickets, and he’d seen hereditary cases of hypophosphatemic rickets. Tebben had even seen a few children in this country with nutritional rickets. We both expected to see the “real” rickets in Bangladesh.
But when we got there, we discovered only a few children with subtle findings of rickets and even fewer with florid cases. What had happened? Why was there no rickets? When we asked a nurse these questions, she answered simply, “Because we do what you said to do when you were here before. With appropriate calcium treatment, kids get better sooner. Parents know that, so they bring the kids in sooner, too. We don’t see many advanced cases any more.”
In Bangladesh, dietary supplementation has proven to be an effective means of prevention.16,17 Similarly, in China, preventive education at the community level has proven effective in decreasing the incidence of rickets.18
Implications for Minnesotans
What does this mean for Minnesotans? Studies have shown that rickets is not just a problem for children in Nigeria or other developing countries. An increasing number of children in the United States have been found to have the condition, including children in our neighboring dairy state.19,20
New imaging modalities are revealing links between adolescent fractures and thinning of the cortex of forearm bones. In addition, colleagues at Mayo Clinic have determined that forearm fractures are 32% to 56% more common in adolescent boys and girls, respectively, now than they were 30 years ago.21 Is this related to changes in children’s activities, to changes in sun exposure with increased use of sunscreens, or to changes in children’s calcium intake because of increased consumption of sugar-sweetened beverages instead of milk?
The bone health of children is an important and relevant issue for physicians in Minnesota. They need to be aware of the new information that has emerged in the last 10 years about how they should treat children with bone diseases, specifically the dual concerns of vitamin D deficiency and calcium insufficiency. They need to understand that rickets is still a problem in this country and around the world. Opportunities clearly remain as we seek to improve the bone health of children—and the adults they are becoming. MM
Philip Fischer is a professor of pediatrics at Mayo Clinic.
*This article was written with the helpful input of Tom D. Thacher (Department of Family Medicine, Jos University Teaching Hospital, Jos, Nigeria), Mark Strand (Evergreen Health Service, Shanxi, China), Salman Kirmani (Division of Pediatric Endocrinology, Mayo Clinic, Rochester, Minnesota), and Peter J. Tebben (Division of Pediatric Endocrinology, Mayo Clinic, Rochester, Minnesota).
The author would like to acknowledge the Thrasher Research Fund and its support of several of the studies mentioned in this paper, the many collaborators around the world, and the children and families who have participated with them in clinical studies.
References
1. Pfitzner MA, Thacher TD, Pettifor JM, et al. Absence of vitamin D deficiency in young Nigerian children. J Pediatr. 1998; 133(6):740-4.
2. Thacher TD, Ighogboja SI, Fischer PR. Rickets without vitamin D deficiency in Nigerian children. Ambulatory Child Health. 1997;3:56-64.
3. Barness LA. Rickets: the chicken or the egg! J Pediatr. 1996;129(6):941-2.
4. Pettifor JM, Ross P, Wang J, Moodley G, Couper-Smith J. Rickets in children of rural origin in South Africa: is low dietary calcium a factor? J Pediatr. 1978;92:320-4.
5. Thacher TD, Fischer PR, Pettifor JM, et al. A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children. N Engl J Med. 1999;341(8):563-8.
6. Bishop N. Rickets today—children still need milk and sunshine. N Engl J Med. 1999;341(8):602-4.
7. Thacher TD, Fischer PR, Pettifor JM, Lawson JO, Isichei CO, Chan GM. Case-control study of factors associated with nutritional rickets in Nigerian children. J Pediatr. 2000; 137(3):367-73.
8. Pfitzner MA, Thacher TD, Pettifor JM, Zoakah AI, Lawson JO, Fischer PR. Prevalence of elevated blood lead in Nigerian children. Ambulatory Child Health. 2000; 6:115-23.
9. Wright NJ, Thacher TD, Pfitzner MA, Fischer PR, Pettifor JM. Causes of lead toxicity in a Nigerian city. Arch Dis Child. 2005;90(3):262-6.
10. Graff M, Thacher TD, Fischer PR, et al. Calcium absorption in Nigerian children with rickets. Am J Clin Nutr. 2004;80(5):1415-21.
11. Fischer PR, Thacher TD, Pettifor JM, Jorde LB, Eccleshall TR, Feldman D. Vitamin D receptor polymorphisms and nutritional rickets in Nigerian children. J Bone Miner Res. 2000;15(11):2206-10.
12. Levine MA, Dang A, Ding C, Fischer PR, Singh R, Thacher T. Tropical rickets in Nigeria: mutation of the CYP2R1 gene encoding vitamin D 25-hyroxylase as a cause of vitamin D dependent rickets. To be presented to the 4th International Conference on Children’s Bone Health, Montreal, June 2007.
13. Thacher TD, Pettifor JM, Fischer PR, Okolo SN, Prentice A. Case-control study of breast milk calcium in mothers of children with and without nutritional rickets. Acta Paediatr. 2006;95(7):826-32.
14. Thacher TD, Fischer PR, Strand M, Pettifor JM. Nutritional rickets around the world: causes and future directions. Ann Trop Paediatr. 2006;26(1):1-16.
15. Fischer PR, Rahman A, Cimma JP, et al. Nutritional rickets without vitamin D deficiency in Bangladesh. J Trop Pediatr. 1999;45(5):291-3.
16. Combs GF, Hassan N, Dellagana N, et al. Rickets prevention by calcium: apparent efficacy of food-based calcium supplementation in Bangladesh. Submitted for publication, 2007.
17. Arnaud J, Pettifor JM, Cimma JP, Fischer PR, Craviari T, Meisner C, Haque S, Convergence Rickets Group. Clinical and radiographic improvement of rickets in Bangladeshi children as a result of nutritional advice. Submitted for publication, 2007.
18. Strand MA, Peng G, Zhang P, Lee G. Preventing rickets in locally appropriate ways: a case report from North China. Int Q Community Health Educ. 2002;21(4):297-322.
19. Weisberg P, Scanlon KS, Li R, Cogswell ME. Nutritional rickets among children in the United States: review of cases reported between 1986 and 2003. Am J Clin Nutr. 2004;80(6Suppl):1697S-705S.
20. Mylott BM, Kump T, Bolton ML, Greenbaum LA. Rickets in the dairy state. WMJ. 2004;103(5):84-7.
21. Khosla S, Melton LJ 3rd, Dekutoski MB, Achenbach SJ, Oberg AL, Riggs BL. Incidence of childhood distal forearm fractures over 30 years: a population-based study. JAMA. 2003;290:1479-85.