CAPENEWS Archive - Bone

-Contributed by Dr. Anju Virmani, New Delhi and Dr. Vijayakumar, Calicut


Pth Assays And Their InterpretationBack to Top
Prasun Deb & Ambrish Mithal (from CAPENEWS 3.2, August 1999)


Over the last 20 years, methods for parathyroid hormone (PTH) measurement have improved vastly, especially due to the availability of better radioimmunoassays (RIA), and the adoption of various other techniques in addition to RIA. Certain aspects of PTH physiology make it a difficult hormone to assay:

  • PTH has a short half-life of 2-4 minutes for the intact hormone.
  • Intact PTH circulates at very low plasma levels: 10-55 ng/L.
  • The hormone undergoes extensive catabolism, both in the parathyroid cells (before secretion) and in the liver. Some of these metabolites are immunologically active (but functionally inactive as they lack the amino-terminal 27 amino acid sequence of intact PTH, considered to be important for bioactivity), and have a longer half-life.
  • The intact PTH is a large (84 amino acid) molecule with at least 5 antigenic segments, thus making it difficult to create antisera which would recognize the entire molecule and not one or more segments.

Two techniques are currently available for PTH measurements:
Radioimmunoassay: Three region-specific RIAs have been used for PTH estimation: the carboxy-terminal, amino-terminal, and the mid-region. Mid-region assays, which employ PTH 44-68 as the radioligand, are the most widely used, since they have a high sensitivity and can differentiate between hypoparathyroidisn of varying severity. However, in addition to intact PTH, these assays also measure various fragments which are secreted by some parathyroid adenomas, and thus are not specific for bioactive intact PTH.

Immunoradiometric Assay (IRMA): The two-site IRMA allows for specific estimation of the intact PTH. This assay uses two antibodies recognizing two different sites of the PTH molecule: the 'capture' antibody which is bound to a solid phase on the sides of the tube, and recognizes a carboxy-terminal epitope in the 44-84 region; and the 'probe' antibody which is labelled, identifies an epitope in the 1-32 segment of the molecule, and detects those captured molecules which bear both epitopes. The antibody molecules are larger than PTH, so they can be radiolabelled at multiple sites, or made 'hotter', enhancing the sensitivity of IRMA.

Other Assays: Two-site assays linked to an enzyme that can generate a colored or fluorocent molecule has been developed, and may become more popular as radioisotopes become costlier. Biological assays have been used experimentally, but the need for tissue slices and immuno-histochemistry precludes their commercial use. Criteria for an

Adequate PTH Assay:

  • It should be sensitive enough to differentiate between normalcy and total hypoparathyroidism (defined as requiring at least 50,000 units/ day of vitamin D to maintain adequate calcium levels).
  • Inter-assay and intra-assay coefficient of variation should be < 10%.
  • Samples should be run at least in duplicates.
  • In RIA, samples should be assayed in two or more dilutions to see whether they dilute out parallel to the standard curve. This helps detect false positive cases, due to displacement of radiotracers by plasma proteins. Such dilutions are not required in IRMA.
  • In RIA, sera from total hypoparathyroid patients should be used to define the zero value.

Collection of samples: PTH samples should be collected on ice, in a pre-cooled syringe. The plasma should be immediately separated and frozen at -70 C, being thawed only for assay. It is advisable to collect the samples in at least 2 aliquots. Samples should be collected after an overnight fast, before 11 am. Values tend to rise during the afternoon, so the upper limit of normal should be raised by about 33% for a sample collected between 11.30 am and 3 pm. PTH is not estimated in nocturnal samples, as an even greater rise in concentration occurs during the night. A simultaneous estimation of serum calcium should be performed.

Confounding factors:

  • Secretion of PTH is episodic, and a raised iPTH with normocalcemia should be verified on a repeat sample. Because of its longer half-life, the mid-region assay is less sensitive to secretory bursts.
  • The various PTH fragments are cleared by glomerular filtration, while intact PTH (iPTH) is cleared by peritubular uptake. Therefore mid region assays are sensitive to declining renal function (GFR < 40 ml/ min causes increased values even before parathyroid hyperplasia occurs), while iPTH is relatively well preserved in early renal impairment, bioactive half life of iPTH doubling only in CRF.
  • Values for PTH in patients with primary hyperparathyroidism (PHPT) may be differentiated from nonparathyroid hypercalcemia by bringing down the calcium level slightly (but not normalizing it). This will reduce high PTH in all other conditions, but high levels persist in PHPT. Similarly PTH values in secondary hyper-parathyroidism will be lowered if treatment is instituted before doing the PTH assay.

PTH assays: availability: Intact PTH assays commonly available in India are marketed by Incstar and DSL. Mid-region assays are also available.

Indications for PTH estimation: PTH estimation is needed in the differential diagnosis of various hypocalcemic and hypercalcemic states, in the neonatal period and later childhood. It should be remembered that much lower calcium levels are considered normal in the neonatal period (as low as 7.6 mg/dL).

Hypocalcemia:

  1. Neonatal hypoparathyroidism
    1. Early Neonatal Hypocalcemia: Hypocalcemia occurring during the first 3 days of life. PTH levels are low, normal, or elevated, along with high calcitonin. It is seen in premature and postmature infants, infants of diabetic mothers (calcitonin is normal), asphyxia (PTH is high), and infants of pre-eclamptic mothers. Exact etiology for hypocalcemia is not known, but a several days' delay in the phosphaturic action of PTH has been described in these infants.
    2. Late Neonatal Hypocalcemia: Tetany occurring between 5-10 days of life, usually with hyperphosphatemia. Infants are often on cow's milk; in addition to high phosphate load in the diet, low phosphate clearance by immature kidneys, transient low PTH levels, and hypomagnesemia are contributory factors.
    3. Neonatal Hypocalcemia: other causes:
      • Infants of mothers with PHPT : for first 2-3 weeks of life;
      • Congenital hypoparathyroidism: DiGeorge syndrome; Kenny- Cuffey syndrome;
      • Infants receiving exchange transfusion;
      • Infants on ventilators, who develop alkalosis.
    4. Hypoparathyroidism: PTH levels are low or undetectable. May be congenital (as above) or acquired (hemosiderosis, post-surgical).
    5. Pseudohypoparathyroidism: high PTH levels, with hypocalcemia and hyperphosphatemia, with or without the physical phenotype of Albright's hereditary osteodystrophy.
    6. Vitamin D deficiency and resistance states: with characteristically high serum alkaline phosphatase, usually do not need PTH estimation for diagnosis, though moderate secondary hyperparathyroidism may develop.)
Hypercalcemia:
  1. Vitamin D related (PTH values suppressed):
    • Vitamin D intoxication
    • Idiopathic hypercalciuria of infancy
  2. PTH related: familial benign hypocalciuric hypercalcemia: inappropriately normal or slightly high PTH in face of high serum calcium levels.
  3. Chronic renal failure with secondary hyperparathyroidism: PTH is usually elevated 2.5-3 times the normal value.
  4. Associated with high bone turnover (PTH levels suppressed): e.g. hyperthyroidism, immobilization, malignancies, or Jansen's metaphyseal chondroplasia.
...

ForumBack to Top
(from CAPENEWS 4.3, Dec 2000):


Question: We often prescribe Vitamin D: when would you prescribe the inexpensive vitamin D3, and when would you use alfacalcidol or calcitriol?

Replies from

Vivek Arya, Hyderabad: I would prefer inexpensive vitamin D in any kind of patient either rich of poor. However, if there is a case of rickets with severe manifestations I would give either alfacalcidiol or calcitriol for about 3 weeks till the action of 1,25 D3 starts and the levels of calcium are maintained. Calcitriol itself is not safe as it may cause hypercalcemia in some cases if overtreated.

V Bhatia, Lucknow: I would use only vit D3 for nutritional rickets/ osteomalacia. For hypoparathyroid-ism, CRF or hypophosphatemic rickets, I use calcitriol or alpha D3. Now there are at least 3 preparations of calcitriol in the market: the cheapest (Cadila) is Rs 8, but alphaD3 of some companies is even cheaper, Rs 5, so I use it where the difference is significant for the patient. One sachet of 60,000 units of D3 is actually costlier than one capsule of calcitriol (0.25 ug), but for hypopara etc, we often need 2 capsules of alphaD3 or calcitriol per day, so the total cost still exceeds that of using D3, where for small children, even 30,000 units may suffice.

RN Mehrotra, Hyderabad : The type of vitamin D used depends upon the indication: in nutritional rickets and prevention of osteoporosis, Vit D3 is the drug of choice, along with calcium salts. (For established osteoporosis, use of 1,25 or alphaD3 is still under investigation.) hypophostemic osteomalacia/ rickets and renal rickets/ renal osteodystrophy require use of 1, 25 D3. In hypoparathyroidism 1,25 D3 or alpha D3 are preferable (if the patient can afford long term costs), otherwise Vit D3 can be used with satisfactory results.

Padma S Menon, Mumbai: I would prescribe vitamin D3 as most of my patients are from lower strata of economic group. They very often require long term treatment (severe HVD), so compliance will be poor if anything else is prescribed.

Vasantha Nair, Kochi: I use alphaD3 or 1,25 D3 whenever I need rapid correction of calcium (eg post thyroid/ parathyroid or other extensive neck surgery) or for long term management of hypoparathyroidism, if the patient can afford the expense. I would rather more often use the least expensive D3 since it is so much cheaper and longer acting, especially for nutritional deficiency. Where price is a consideration, even in renal/ hepatic failure, it has been used in very high doses, though of course it is not as effective. Anon.

Vitamin D Deficiency In Young InfantsBack to Top
Anju Seth (from CAPENEWS 7.1, April 2003)


Nutritional rickets due to the deficiency of Vitamin D and/or calcium is widely prevalent, especially in the developing nations of the world (1). It is usually diagnosed in the later half of infancy or during the next 2 years or so, on the basis of the characteristic clinical, biochemical and radiological features. The prevalence and manifestations of Vitamin D deficiency during the neonatal period and early infancy has received little attention so far. However, available literature suggests that it is likely to be equally prevalent albeit in a more subtle form.

Mother-infant Vitamin D relationship

A close link exists between the Vitamin D status of the mother and her offspring. A baby born to a woman with poor stores even without any overt features of osteomalacia is likely to have low Vitamin D stores in turn. Low serum 25(OH)D3 levels in pregnant women are associated with low levels in cord blood and the neonate (2-4). The breast milk of these women is also poor in Vitamin D (5). Thus, the baby born with low stores continues to receive sub-optimal daily supply of Vitamin D, perpetuating the deficiency. Maternal deficiency is found to be associated with rickets in unsupplemented breast fed infants (6,7). Supplementing pregnant and lactating women is reported to improve the Vitamin D status of their infants (8-10).

Magnitude of the problem

While most of the literature pertaining to maternal/ neonatal Vitamin D deficiency is from America or Europe, the population at risk of deficiency in these studies has predominantly been Asian migrants (3, 11-16). Thus in UK, osteomalacia is seen most commonly among Asians (16), and much lower 25(OH)D3 levels have been reported among pregnant Asian women vs. their non-Asian counterparts (14). In a study from Leeds, 81% of the newly delivered Asian women, 68% of the cord blood samples and 36% of the newborn babies had Vitamin D levels in the osteomalacic range (< 25nmol/L ie < 10 µg/L) (3). This deficiency is not restricted to the under-nourished section of society only. Occult osteomalacia and low Vitamin D levels have been reported in healthy and pregnant women in Pakistan (17), Saudi Arabia (7), Ethiopia (13) and recently, India (18). Likewise, infants with hypocalcemic seizures due to Vitamin D deficiency from Pakistan have had a good nutritional status (19). However, the magnitude of the problem in these countries has not been quantified. This is mainly due to the fact that most affected women and children have sub-clinical deficiency and thus escape detection (3,5). Assessment of the prevalence depends upon biochemical assays, the most specific being plasma 25(OH)D3 levels, which is not readily available. Nevertheless, available literature suggests that the problem is likely to be significant, since very few women receive Vitamin D supplements during pregnancy or lactation, and the majority breastfeed their infants. Even infants receiving top milk may be affected since most commercially available milk is not fortified with Vitamin D. Other contributing factors include inadequate sun exposure, dark complexion interfering with Vitamin D synthesis in the skin, poor dietary intake of Vitamin D and calcium, and frequent pregnancies draining the already compromised stores (5,10,19).

Clinical Features:

As mentioned earlier, most babies born with low stores are likely to be aymptomatic. In those with symptoms, the most common manifestation is hypocalcemic seizures. The Leeds study (3) reported that 2% of Asian babies had tetany in the first few days of life vs. 0.03% non-Asian babies. In a Pakistani study (19), of 96 infants with seizures, the cause was hypocalcemia in 65, in 50 of whom ALP levels were also elevated. 25(OH)D3 levels were measured in 15 infants and were found to be low in all (7.5 + 3.8 µg/L) while the levels were undetectable in their mothers. Notably, only 2 infants, ages 12 and 14 months, had clinical features of rickets; the X-ray was normal in a third of the children. In a recent Indian study on the profile of hypocalcemic children (20), 15 of 29 had elevated parathormone levels; 11 of them had presented with seizures under 3 months of age. These children were diagnosed as cases of pseudo-hypoparathyroidism (PHP). Though the serum 25(OH)D3 levels were not measured, the authors conceded that a number of these babies could actually be having Vitamin D deficiency. Some infants with Vitamin D deficiency may have craniotabes or widened anterior fontanelles. However, frank rickets with characteristic chest deformities, craniotabes, wide fontanelle, and X-ray changes, is much less common (15, 21,22).

Prevention: Need and strategies

It is clear from the foregoing discussion that a large number of apparently normal infants are likely to have a borderline Vitamin D status. Though they do not seem to be adversely affected, they are at a high risk of developing rickets, especially during the winter months when their exposure to the sun further decreases. Thus, most infants in the Pakistan study (19) presented with seizures during winter, and low plasma 25(OH)D3 levels in infants during winter have been reported from Norway (23). The status of malnourished children is also likely to be compromised. Therefore, most Western experts are in favor of routine supplementation of exclusively breast fed infants with 400 IU of Vitamin D, regardless of maternal supplementation during pregnancy (10,12,23,24). This is even more relevant for children from developing nations, where perhaps the recommendation should include top fed infants also, due to poor availability and consumption of Vitamin D fortified foods. In addition, attempts should be made to improve the Vitamin D status of pregnant and lactating women by disseminating information regarding the importance of adequate sun exposure and routine supplementation with 400 IU of Vitamin D. Improving the availability and consumption of fortified food and milk products is likely to benefit at least those who are not very poor, since Vitamin D deficiency is not limited to the poor or undernourished only. These approaches are inexpensive and not difficult to implement, and have been shown to prevent deficiency and cause no harm (4,9,10). In addition, hypocalcemia and Vitamin D deficiency should be considered a possibility in any infant presenting with seizures.

References:

  1. Bhattacharya AK. Nutritional rickets in the tropics. Simopoulos AP (ed.) Nutritional triggers for Health and Disease. Basil: Karger; 1992, 140-197.
  2. Birbeck JA and Scott HF. 25 hydroxy cholecalciferol serum levels in breast fed infants. Arch Dis Child 1980, 55: 691-695.
  3. Heckmatt JZ, Peacock M, Davies AEJ et al. Plasma 25-hydroxyvitamin D in pregnant Asian women and their babies. Lancet 1979,2: 546-549.
  4. Cockburn F, Belton NR, Purvis RJ et al. Maternal Vitamin D intake and mineral metabolism in mothers and their newborn infants. Br Med J 1980,281: 11-14. Rothberg AD, Pettifor JM, Cohen DF, Sonnendecker EWW and Ross FP. Maternal infant Vitamin D relationships during breastfeeding. J Pediatrics 1982,101(4): 500-503.
  5. Edidin DV, LeVitaminsky LL, Schey W, Dumbovic N, Campos A. Resurgence of nutritional rickets associated with breast feeding and special dietary practices. Pediatrics 1980,65: 232-235.
  6. Sedrani SH, Al-Arabi K, Abanmy A, Elidrissy A. Vitamin D status of Saudis: Seasonal variations. Are Saudi children at risk of developing Vitamin D deficiency rickets? Saudi Med J 1992,13: 430-434.
  7. Alahouhala M, Koskinen T, Koivula T, and Visakorpi J. Maternal compared with infant Vitamin D supplementation. Arch Dis Child 1986, 61: 1159-63.
  8. Brooke OG, Brown IRF, Bone CDM, Caster ND et al. Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth. Br Med J 1980,280: 751-754.
  9. Finberg L. Human milk feeding and Vitamin D supplementation-1981. Pediatrics 1981,99: 228-229.
  10. Belton NR, Grindulis H, Scott BA and Wharton BA. Vitamin D deficiency in Asian children in Britain- a case for prophylactic supplementation? In, NormanAW, Schaefer K, Grigoleit HG. Von Herrath D (eds.) Vitamin D: Chemical, biochemical and clinical update. Berlin, Walter de Gruyter , 1985: 579-580.
  11. Brooke OG, Butters F and Wood C. Intrauterine Vitamin D nutrition and post natal growth in Asian infants. Br Med J 1981, 283: 1024.
  12. Fogelman Y, Rackover Y, Luyboshitzky R. High prevalence of Vitamin D deficiency among Ethiopian women migrants to Israel: Exacerbation during pregnancy and lactation. Isr J Med Sci 1995,31: 221-224.
  13. Dent CE, Gupta MM. Plasma 25-hydroxyvitamin D levels during pregnancy in Caucasians and in vegetarian and non-vegetarian Asians. Lancet, 1975,2: 1057-1060.
  14. Ford JA, Davidson DC, McIntosh WB, Fyfe WM and Dunnigan MG. Neonatal rickets in Asian Immigrant population. Br Med J 1973, iii : 211-12.
  15. Goel KM, Logan RW, ArneilGC, Sweet EM, warren JM, Shanks RA. Florid and sub-clinical rickets among immigrant children in Glasgow. Lancet 1976,1:1141-1145.
  16. Rab SM, Baseer A. Occult osteomalacia amongst healthy and pregnant women in Pakistan. Lancet 1976, 2: 1211-1213.
  17. Goswami R, Gupta N, Goswami D, Marwaha KK, Tandon N and Kochupillai N. Prevalence and significance of low 25-hydroxyvitamin D concentration in healthy subjects in Delhi. Am J Clin Nutr 2000,72: 472-475.
  18. Ahmed J, Atiq M, Iqbal J, Khurshid M and Whittaker P. Vitamin D deficiency rickets in breast fed infants presenting with hypocalcemic seizures. Acta Paediatr 1995, 84: 941-942.
  19. Sharma J, Bajpai A, Kabra M and Menon PSN. Hypocalcemia- Clinical, biochemical, radiological profile and follow up in a tertiary Hospital in India. Indian Pediatrics 2002, 39: 27-281.
  20. Teotia M, Teotia SP and Nath M. Metabolic studies in congenital Vitamin D deficiency rickets. Indian J Pediatr 1995, 62: 55-61.
  21. Moncrieff M, Fedahursi TO. Congenital rickets due to maternal Vitamin D deficiency. Arch Dis Child 1974,49: 810-811.
  22. Markestad T. Effect of season and Vitamin D supplementation on plasma concentration of 25- hydroxyvitamin D in Norwegian infants. Acta Paediatr Scand 1983,72: 718-721.
  23. Ala-Houhala M. 25hydroxy Vitamin D levels during breast feeding with or without maternal or infantile supplementation of Vitamin D. J Pediatr Gastro Nutr 1985,4: 220-226.

Rickets In Young Children Vs Adolescents: Varying Role Of Calcium Intake And Vitamin DBack to Top
Dr V Bhatia (from CAPENEWS 7.1, April 2003)


Some of our DM students and I, along with collaborators from the departments of Pediatrics, Rehabilitation and Obs-gyne in KGMC (now CSMMU), have recently completed studies on the serum Vitamin D, sun exposure and dietary calcium status in young children with rickets, adolescents with rickets / osteomalacia, healthy childhood and adolescent controls, and rural and urban pregnant women.

Calcium intake, sun exposure, serum alkaline phosphatase and 25-hydroxyvitamin D (OHD) were studied in 24 young children and 16 adolescents with rickets/ osteomalacia, and compared with values obtained in 34 childhood and 19 adolescent controls. Young children with rickets had lower calcium intake as compared to controls, but similar sun exposure and serum Vitamin D levels. Mean Vitamin D level of the childhood rickets group was in the normal range, with 16 of the 24 having values above the "rachitic" cut off of 10 ng/ml. In contrast, only 1 of the 16 adolescent patients had serum 25 OHD above 10 ng/ml. This group also had significantly lower sun exposure versus the childhood rickets as well as both control groups.

Adolescent patients had a long duration of disease before the correct diagnosis, due to previous misdiagnosis as rheumatic fever, ankylosing spondylitis, primary neuromuscular disease, and tubercular hip joint. This was due to the severe bone pains, proximal muscle weakness and abnormal gait these patients had. Noteworthy also was the fact that all patients in this unselected group of adolescent rickets were girls, underscoring the importance of poor sun exposure in the etiology of adolescent rickets in our country. Though the follow up rate during therapy was poor in our young children, those treated with calcium alone healed radiologically as well as biochemically. In contrast, no adolescent patient improved with calcium treatment alone (though the follow up in this group was excellent), and randomisation to calcium alone versus calcium with Vit D treatment was stopped after 8 patients and the rest treated straightaway with the combination.

We concluded that poor calcium intake is universal among young children as well as adolescents with rickets, and that Vit D deficiency is important to bear in mind in adolescents even in a sunny country like India, due to social factors. This second factor is easily preventable by education. Further, overt rickets is the tip of the iceberg. Poor vitamin nutrition in adolescence has connotations for impaired pubertal growth, adult osteoporosis, and fetal and infantile hypovitaminosis D. These studies are accepted for publication in Journal of Tropical Pediatrics and the National Medical Journal of India.

Our results in the 200 pregnant women are yet to be fully analyzed, but suggest that Vit D deficiency is common in both urban and rural booked and unbooked women. Calcium intake is lower than RDA for pregnancy, even in booked women. There is a strong correlation between maternal and cord blood serum Vitamin D.

The implications of fetal and neo-natal hypovitaminosis D include neonatal hypocalcemia, poor infantile growth and enamel formation, and most importantly, increased frequency of lower respiratory tract infections.

Excerpts From MeetingsBack to Top
Sudha Rao (from CAPENEWS 7.1, April 2003) in Pedicon2003


Dr Vaman Khadilkar spoke on the role of bisphosphonates in osteogenesis imperfecta. Drugs that inhibit bone resorption, such as calcitonin and bisphosphonates, are likely to be useful in conditions of increased bone resorption. Beneficial effects on bone density have been reported in idiopathic juvenile osteoporosis, steroid induced osteoporosis, osteogenesis imperfecta, and polyostotic fibrous dysplasia. In his experience, use of both oral (alendronate) and intravenous (pamidronate: 1mg/ kg/ day iv every three months) bisphosphonates has shown promising response with reduction in symptoms like bone pains and fracture incidence, and improvement in mobility, ambulation, and bone mineral density. He pointed out that care must be taken when using these drugs to ensure provision of adequate calcium and vitamin D. He emphasized that the use of these drugs in children was still in the experimental stages, therefore at present they should be used only by centers with expertise in the area, rather than by general pediatricians.

International Update: Bangalore 2004Back to Top
(from CAPENEWS 8.3, December 2004)


Dr MZ Mughal, in clinical approach to rickets, mentioned a Arch Dis Child 2002 report, showing the significantly lower serum Vitamin D (mean 11.7 ng/ ml) and higher serum PTH levels (mean 25 ng/ ml) in the polluted Mori Gate area of Delhi compared to cleaner Gurgaon (28.2 and 13.2 ng/ ml respectively). He emphasized that even prolonged breast feeding can cause rickets. The problem could be primarily due to calcium deficiency (eg in Bangladesh), Vitamin D (Vit. D) deficiency, or both, especially in adolescents. Other points he made:

  • The interpopliteal distance between the dimples on the back of knee can be used as a clinical measure (to have a landmark for successive measurements).
  • Even though Vit. D deficiency is defined as levels < 20ng/ml, rickets occurs only with levels < 5 ng/ ml.
  • Adequacy of rickets treatment is best monitored by checking PTH levels. If PTH is too expensive, it is better to rely on serum phosphorus levels rather than on alkaline phosphatase: as the phosphaturic effect of PTH wanes, the serum phosphorus rises.
  • Several dental changes occur in rickets: delayed eruption, enamel hypoplasia, healing rings, and especially in X linked hypophospha-temic rickets (XLH), multiple dental abscesses.
  • Alpha calcidol can be given once a day in XLH whereas calcitriol has to be given twice a day.
  • The calcium content of vit. D deficient mothers is 10% less than D replete mothers.
  • Sweating is a common feature of Vit. D deficiency.
In a talk on juvenile osteo-porosis, Dr Mughal said:
  • Bone density was only one of the determinants of bone strength, the others being size and shape of the bone, and fatigue damage.
  • Peak bone mass is achieved by age 21 yrs in women and 23 yrs in men; with 40% bone mass laid down in the 4 years of perimenarche.
  • Interpretation of BMD in children is difficult: they are still growing, smaller bones look more osteo-porotic, and shorter persons (eg children with growth disorders) would have spuriously lower BMDs.
  • Areal BMD is bigger for bigger bone size. A correction factor must be applied to get volumetric density.
  • BMD data from different models of machines cannot be compared.
  • Excess dietary salt intake causes hypercalciuria and thus increased net calcium losses. Fizzy drinks may also perhaps increase fracture risks.
  • Causes of juvenile osteoporosis include: osteogenesis imperfecta, Ehler Danlos syndrome, steroid therapy, JRA, inflammatory bowel disease, cystic fibrosis, chronic liver disease, cerebral palsy and muscle disorders (due to immobilization), anorexia nervosa and galactosemia (due to hypogonadism), and juvenile idiopathic osteoporosis.
  • Bisphosphonates decrease bone resorption by osteoclasts, thus increasing bone density. They should be avoided in adynamic bone disease, eg in renal osteodystrophy.
  • Bisphosphonate use in children may lead to persistence of spongiosa, and thus potentially lead to weaker bones in the long run. Other troublesome questions: risk of osteosclerosis in high doses? teratogenic potential? When should therapy be stopped? For a good review on the crucial topic of glucocorticoid induced osteoporosis, he recommended Bianchi, Arthr Rheum 2000; 43: 1960-66.
Dr Prisca Colaco, discussing renal tubular acidosis (RTA), emphasized the need to correct hypokalemia before the bicarbonate, and that the urinary anion gap helps differentiate between distal RTA (positive anion gap) and metabolic acidosis due to hypovolemia such as diarrhea.

International Update: Mumbai 2008Back to Top
Cape News April 2008, 12-1


Rickets as a manifestation of tissue phosphorous deficiency:
An interesting perspective on rickets was proposed: that tissue phosphorous deficiency plays a central role in etiology of rickets by failing the apoptosis of the terminal hypertrophic chondrocytes. (Z Hochberg)

Calcium, vitamin D nutrition in adolescent girls:
Calcium deficiency alone can also cause rickets and osteopenia. Severe dietary deficiency of absorbable calcium leads to elevated PTH, which is known to increase synthesis of 1,25(OH)2D3, which in turn degrades 25(OH)D3 to inactive 24,25(OH)D3, thereby depleting body stores of 25 OH D3. (V Khadilkar)

Vitamin D deficiency, pregnant women and neonates:
Vitamin D deficiency is common in among mothers and their newborns in India even after prolonged sun exposure. Possible contributing factors could be the traditional clothing and inadequate skin exposure, skin pigmentation, pollution, and low dietary calcium. Hypovitaminosis D during pregnancy can lead to neonatal hypocalcemia, infantile rickets, poor growth, lower respiratory tract infections, and fetal programming leading to persisting osteopenia. There is a real need to supplement pregnant women with vitamin D to avoid these problems in their babies.
Intervention and possible formulation of public health policy is needed. The minimum effective dose needs to be established through properly designed studies. (V Bhatia)
In a novel and interesting study, two types of doses of vitamin D (60,000 U vs 240,000 U) were supplemented to pregnant females and results compared with unsupplemented controls. Both doses of vitamin D provided protection against neonatal biochemical rickets (babies' cord blood alkaline phosphatase was significantly lower with both doses), and higher, anterior fontanelle significantly lower in supplemented group). The difference in the babies' anthropometry persisted till 9 months of age! (P Kalra, V Bhatia)

Hypercalcemia, hypervitaminosis D: In more than 60% of children (1.5-18 months age) presenting with hypercalcemia, the cause was hypervitaminosis D. Mega-doses of vitamin D (9-20 lac U) had been given inappropriately to these children for failure to thrive. Spreading awareness against this practice can easily prevent a majority of cases of hypercalcemia. (S Rao)

1α hydroxylase def. rickets: Rickets due to 1α hydroxylase deficiency can present with normal 1,25(OH)2D levels. Therapeutic response is seen with the recommended dose of 1,25(OH)2D supplementation. Therapeutic trial of 1,25(OH)2D should be given in a clinically compatible case where other causes have been ruled out. (Case discussion: L Priyambada, V Bhatia, Z Hochberg, CJ Munns)

  • Normal urine calcium/ creatinine ratio is higher in the newborn period (0.9) and becomes 0.25 by 2 years of age.
  • High frequency low magnitude biomechanical bone stimulation is a new and exciting modality with potential to improve both bone strength and muscle function especially in childhood osteoporosis. (CJ Munns)

Clippings For CapenewsBack to Top
Ram Murty Shastry, Goa from CAPENEWS 8.3, December 2004


Hypocalcemia due to vitamin D deficiency in exclusively breast-fed infants (S Balasubramanian et al, Indian Pediatrics, March 2006)

In a study of 50 infants and children with hypocalcemic seizures, in 13 exclusively breastfed infants < 6 months of age seizures were due to vitamin D deficiency. All babies were born at term, with normal nutritional status, and no vitamin D supplements. All these infants had hypocalcemia, markedly raised alkaline phosphatase (SAP: mean 1250 IU/L), low vitamin D levels (mean 3.8ng/ml) and elevated parathormone levels (mean 106 pg/ml), with hypophosphatemia in 9/13. Only 2 had radiological signs of rickets; 2 had dilated cardiomyo-pathy, and one had myelofibrosis. Mothers of all infants had low levels of 25OHD3, but none had any overt clinical abnormality; 5 reported reduced sunlight exposure due to religious reasons. All these infants were treated with a single dose of injection vitamin D3 6 lakh units, followed oral vitamin D 400 IU/day, and mothers advised to have sun exposure for themselves and the infants. IV calcium was given until serum calcium normalized (mean 3 days), followed by oral calcium supplements (50 mg/ kg/ day) for 2 months in all. SAP normalized over 25 days to 3 mo (mean 2 mo).

Comments:

This report emphasizes the need to supplement vitamin D in exclusively breastfed infants (as recommended by American Academy of Pediatrics in Pediatrics 2003; 111: 908-910) and also to encourage sunlight exposure in them and their mothers. This supplementation is irrespective of the mothers' serum 25OHD status. Furthermore, all the mothers in this study were found to be biochemically deficient in vitamin D. Breast milk from a vitamin D replete mother contains 20-60 IU/L of vitamin D, while the recommended intake for infants is 200 IU/day. 25OHD3 crosses the placenta readily and with a half life of 3 weeks, provides some protection against vitamin D deficiency for a couple of months even if the young infant does not receive vitamin D.

A Case Of IJOBack to Top
V Bhatia, SGPGI, Lucknow Goa from CAPENEWS 8.3, December 2004


A 13 yr old girl presented with history of fall from a ladder 2 ½ years back, and onset of lower back pain since that time. The trauma was likely minimal, and she was not immobilised at any time then or thereafter. Spine X-rays taken then showed osteoporosis and anterior wedge fracture of L1-3 and T12. She had no further fractures, and was not given any specific treatment then, but was given a spinal brace about 2 months ago. She gave no history of fever, contact with open TB or past TB herself; no documented anemia or bleeding tendencies; no history suggestive of hyperthyroidism, malabsorption, seizures, or joint disease; no significant medication apart from injections of vitamin D in 2003 and 2004; and no significant family history. She had entered puberty about 1 ½ years before presentation. She was 45 kg, 148 cm, normotensive, afebrile, with no lymphadenopathy or organomegaly, no evidence of Cushing syndrome. Pubertal staging was breast stage 3, pubic hair stage 2. There was no evidence of Marfan syndrome in her body proportions or hand examination (no blue sclerae; no hyperextensibility of joints). Her lab reports were as follows:
  • hemoglobin 13gm%
  • TLC 7500/cumm
  • N70 L26 E2 M2
  • SGPT 50 U/L
  • creatinine 0.5 mg%
  • serum calcium 9.0, 10.1, and 10.8 mg%
  • PO4 3.4, 4.4, and 5.2mg%
  • alkaline phosphatase 538 and 594 U/L (normal for adults below 250 IU/L)
  • Serum 25OH
  • Vitamin D was 77.5 ng/ml (normal)
  • PTH 54 pg/ml (normal 9-55 pg/ml)
  • thyroid function tests
  • abdominal ultrasound examination normal.

The radiologist reported that the spine X-rays (lateral view) showed moderately severe wedge fracture deformities of L1 and L3. The intervening intervertebral disc spaces were of normal height and adjacent end plates were intact. No gross retropulsion was seen at either level. The appearances were those of simple fracture with no suggestion of underlying pathology except osteopenia. A diagnosis of IJO (idiopathic juvenile osteoporosis) was made. Though this is a self-limiting condition, in view of the severe nature of her osteoporosis, we opted to offer bisphosphonate therapy for a short period until we achieved normalization of density. She was given pamidronate infusions at a dose of 45 mg per dose for 3 consecutive days, once in 3 months, for 2 years. The initial bone mineral density as well as that after 2 years is in the table.

Comment: This case highlights several points worth remembering:
  1. IJO is a diagnosis of exclusion, and a thorough history and examination should be performed to rule out important causes of osteoporosis.
  2. When some vertebrae are collapsed, the conventional L1-L4 mean bone density should not be considered, and only individual vertebrae which are spared should be taken into account (as can be appreciated in the discrepantly high density in L1 in 2004).
  3. The rate of change of density is higher than that seen in a 2 year period in this age group. The improvement could be spontaneous, or treatment related, or both. Rates of change in the pediatric age group in patients on antiresorptive therapy are far higher than those obtained in adults, and the natural gain with age should be kept in mind while interpreting improvements. The normal rates of change in childhood are of the order of 4-5% and during puberty 8-10%.
  4. T scores are not mentioned in pediatric bone density reporting, as peak bone mass has not yet been achieved. (T score is the number of standard deviations (SDs) the BMD is below reference peak bone mass for sex whereas Z score is the number of SDs the BMD is below reference bone density for age and sex). Even interpretation of Z scores may be fraught with danger. BMD depends on the size of the bone. The size of the bones is a girl with chronic disease, and possibly delayed puberty, is likely to be smaller, and thus may not be comparable to that of a normal girl of the same age.
A recent study published in J Bone Miner Res (Hartikka et al 2005) has thrown some light on the etiology of IJO. Three of 20 patients had mutations of the LDL receptor-related protein 5 (LRP5). Affected family members of one proband also carried the mutation. No patient carried the collagen gene Coll 1 A1 and A2 mutations seen in osteogenesis imperfecta.