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PubMed1985

Vitamin D metabolism and osteomalacia in cystic fibrosis.

A 25-yr-old black man with cystic fibrosis and cirrhosis developed symptoms of osteomalacia and hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and low circulating 25-hydroxyvitamin D (25-OHD). Serum 1,25-dihydroxyvitamin D (1,25-[OH]2D) was within the normal range. Iliac crest bone biopsy confirmed the diagnosis of osteomalacia. Oral administration of 50,000 IU of vitamin D2 failed to relieve symptoms or raise serum 25-OHD levels to normal. Intramuscular vitamin D2, 10,000 IU every 8-12 week, improved symptoms, raised serum 25-OHD to normal, and increased circulating 1,25-[OH]2D to values five times normal. Over the next 10 mo circulating 1,25-[OH]2D remained elevated despite normalization of serum calcium, phosphorus, and parathyroid hormone. Repeat bone biopsy 1 yr after parenteral vitamin D showed healing of the osteomalacia. Malabsorption of vitamin D appears secondary to profound steatorrhea due to pancreatic insufficiency and secondary biliary cirrhosis. Although extensive hepatocellular disease was present, hepatic conversion of vitamin D to 25-OHD was intact. Both high and low circulating 1,25-[OH]2D levels during active osteomalacia have been reported; initially, the level was in the normal range and higher values in this patient occurred with repletion of 25-OHD substrate. This study shows that symptomatic osteomalacia may be a major manifestation of cystic fibrosis in those patients surviving into adulthood. Measurements of serum 25-OHD in cystic fibrosis patients may identify those who should receive supplemental vitamin D.

Adult↗

PubMed1986

Acidosis-induced osteomalacia: metabolic studies and skeletal histomorphometry.

The pathogenesis of osteomalacia was investigated in three patients with chronic metabolic acidosis. Serum levels of parathyroid hormone and vitamin D metabolites were measured, and bone biopsy specimens were analyzed after double tetracycline labeling. Parathyroid hormone concentrations were normal in patients 1 and 3 and slightly elevated in patient 2. Vitamin D metabolism was undisturbed. Static indicators of bone remodeling substantiated the diagnosis of osteomalacia in each case. In patient 1 fluorescent microscopy revealed no evidence of tetracycline uptake. In patients 2 and 3 active mineralization was evident at all osteoid seams, but because double labels were rare, the mineral apposition rate appears to have been substantially reduced in most bone-forming units. Our results indicate that acidosis-induced osteomalacia, unlike that due to vitamin D deficiency, may be associated with mineral deposition at every possible site. Nevertheless, like other causes of osteomalacia, metabolic acidosis prevents mineral apposition at a normal rate even if mineral deposition is ubiquitous. We suggest that titration of newly deposited phosphate causes the observed impairment of mineral apposition and ultimately leads to osteomalacia.

Acidosis↗

PubMed1990

The effects of the major vitamin D metabolites upon the resolution of osteomalacia in uremic adult rats.

We have previously shown that an osteomalacia dependent upon both a low phosphorus diet and uremia (five-sixth nephrectomy) can be produced rapidly in rats. This is associated with hypophosphatemia and elevated 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). In order to investigate the role of exogenously administered vitamin D metabolites upon the resolution of this osteomalacia, 72 male Sprague Dawley rats weighting 320 +/- 20 g were subjected to a two-step, subtotal nephrectomy and subsequently fed a diet with low (0.03%) phosphorus (LP) for seven days. Groups of six rats each were then either continued on the LP diet, or switched to a nutrient-matched diet with normal (0.3%) phosphorus (NP) for an additional 10 days. During this time, the rats were infused daily with either: 27 ng 1,25(OH)2D3; 81 ng 24,25 dihydroxyvitamin D3 (24,25(OH)2D3); 135 ng 25 hydroxyvitamin D3 (25(OH)D3); both 27 ng 1,25(OH)2D3 and 81 ng 24,25(OH)2D3; or placebo. Dietary phosphorus repletion was found to reverse the osteomalacia by decreasing the growth plate thickness, the osteoid surface and volume, the osteoid maturation time, serum calcium, and plasma 1,25(OH)2D3, and by increasing the mineralizing surface, bone formation rate, and serum phosphorus. The osteomalacia was also reversed in phosphorus-repleted rats treated with 24,25(OH)2D3, with no additional effects attributable to the 24,25(OH)2D3 itself. Osteomalacia in phosphorus-repleted rats treated with 25(OH)D3 or 1,25(OH)2D3 was only partially reversed; healing was interpreted to be impaired by the elevated plasma 1,25(OH)2D3 levels present in these rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2004

The mineralization index--a new approach to the histomorphometric appraisal of osteomalacia.

The histomorphometric diagnosis of osteomalacia depends on the conjunction of two or three independent criteria but for several reasons, both clinical and pathophysiologic, it would be useful to have a single index of severity. Accordingly, using an extensive library of normal values in 143 healthy women, we constructed the mineralization index (MI), defined as [osteoid thickness (O.Th) (microm) + osteoid volume/bone volume (OV/BV) (%)] x 1.15 - osteoid mineralization rate (%/day) - [bone formation rate/bone surface (BFR/BS) (microm3/microm2/year) x 0.15]. MI was normally distributed with mean 8.0, SD 3.3, and range 0-15 (arbitrary units); it was unaffected by race, menopausal status, age or bone turnover, and was slightly lower in osteoporotic patients with nontraumatic vertebral fracture than in healthy white postmenopausal women (6.83 vs. 7.95). In hypovitaminosis D osteopathy (HVO) stage I, MI was normal in 18/26 cases (70%; HVOia), demonstrating more rigorously than before that osteoid accumulation is initially due entirely to secondary hyperparathyroidism and increased bone turnover. In the remaining 30% (HVOib), MI was increased, indicating the onset of impaired mineralization while bone formation was still increased and before the appearance of osteomalacia. In secondary hyperparathyroidism due to renal bone disease, 10/20 cases (50%) had normal MI and higher BFR than in HVOia (93 vs. 32), and there was a significant inverse correlation between MI and BFR. In patients with osteomalacia according to current criteria, MI ranged from 29.2 to 166.5; an MI of 30 had high sensitivity and specificity for the diagnosis of osteomalacia. Including all patients with HVO, there was a significant (P < 0.001) inverse correlation between MI and calcium x phosphate product, but the unexplained variance of >70% suggests that vitamin D deficiency impairs mineralization by multiple mechanisms. We conclude that the MI clarifies the early effects of vitamin D deficiency on bone and the relationship between different components of renal bone disease simplifies the histologic diagnosis of osteomalacia and may contribute to its management, and explicates the mechanisms of mineralization.

Age Factors↗

PubMed2000

Osteomalacia due to vitamin D depletion: a neglected consequence of intestinal malabsorption.

PURPOSE: Osteomalacia due to vitamin D depletion is believed to be rare in the United States because of the routine fortification of milk and other dairy products with vitamin D. We present a series of patients with histologically verified osteomalacia due to vitamin D depletion to emphasize the need for more careful and systematic surveillance of patients at risk of this metabolic bone disease. METHODS: Between 1989 and 1994, 17 patients with osteomalacia due to vitamin D depletion were seen in the Bone and Mineral Division of Henry Ford Health System, Detroit. All patients had a transiliac bone biopsy after in vivo double tetracycline labeling. Biochemical indexes of vitamin D nutritional status, parathyroid function, markers of bone turnover, and bone mineral density were assessed at the time of bone biopsy. The duration of symptoms, the lag between the cause of vitamin D depletion and the development of symptoms, and the radiologic findings were recorded. RESULTS: Osteomalacia was suspected by the referring physician in only 4 of the 17 patients, although a gastrointestinal disorder that can lead to vitamin D depletion was present in every patient. Thirteen of the patients had sustained at least one osteoporotic fracture (wrist, spine, or hip), and most had low appendicular and axial bone mineral density. All patients had one or more biochemical abnormalities consistent with vitamin D depletion. In 4 patients, a progressive rise in the serum alkaline phosphatase level was recorded but was not investigated until the patient presented with bone pain, muscle weakness, or fracture. CONCLUSIONS: Osteomalacia due to vitamin D depletion appears not to be suspected or diagnosed promptly in susceptible patients, perhaps because their physicians were not sufficiently aware of this condition.

Adult↗

PubMed1978

Osteomalacia after small-intestinal resection.

Histological examination of bone from 25 patients with small-intestinal resection showed that 9 (36%) had osteomalacia, which was severe in 5 and mild in 4. The serum-alkaline-phosphatase concentration was raised in all patients with severe osteomalacia, but serum calcium, phosphate, and alkaline-phosphatase concentrations were normal in the 4 patients with mild disease, 2 of whom had symptoms. Osteomalacia was diagnosed radiologically in only 3 patients. Osteomalacia appears to be commoner in patients with small-intestinal resection than has previously been thought, and bone biopsy is essential if all cases are detected. Although high-dose parenteral vitamin-D therapy is usually effective in the treatment of osteomalacia after small-intestinal resection, our findings showed that oral vitamin-D metabolites and their analogues may also be effective. This has important practical advantages.

Administration, Oral↗

PubMed1996

High fluoride intakes cause osteomalacia and diminished bone strength in rats with renal deficiency.

Renal insufficiency is known to increase plasma fluoride levels, which may increase the risk of fluorosis and osteomalacia. The purpose of this study was to determine the effects of fluoride on skeletal fragility and mineralization in renal-deficient animals. We evaluated the skeleton of rats with surgically induced renal deficiency (4/5 nephrectomy) that were chronically exposed to fluoridated water at concentrations of 0, 5, 15, and 50 ppm for a period of 6 months. The chosen fluoride doses caused plasma fluoride levels equivalent to those in humans consuming fluoridated water levels of 0, 1, 3, and 10 ppm, respectively. Animals with renal deficiency drank about 60% more water and excreted 85% more urine than control animals. Glomerular filtration rate (GFR) was decreased 68% and plasma BUN was increased fourfold in rats with renal deficiency. Plasma fluoride was strongly correlated with 1/GFR and was greatly increased by renal deficiency in all animals consuming fluoridated water. There was a strong positive, nonlinear relationship between plasma fluoride and bone fluoride levels, suggesting nonlinear binding characteristics of fluoride to bone. The amount of unmineralized osteoid in the vertebral bone was related to the plasma fluoride levels. Vertebral osteoid volume was increased over 20-fold in animals with renal deficiency that received 15 or 50 ppm fluoride, suggesting osteomalacia. Should osteomalacia be defined as a tenfold increase in osteoid volume, there appeared to be a threshold plasma fluoride level of about 20 micromol/L, above which osteomalacia was observed consistently. This plasma fluoride level was not achieved in control rats regardless of fluoride intake, nor was it achieved in renal-deficient rats receiving 0 or 5 ppm fluoride. A fluoride concentration of 50 ppm reduced femoral bone strength by 11% in control rats and by 31% in renal-deficient rats. Vertebral strength also was decreased significantly in renal-deficient rats given 50 ppm fluoride. In conclusion, fluoridated water in concentrations equivalent to 3 and 10 ppm in humans, caused osteomalacia and reduced bone strength in rats with surgically-induced renal deficiency.

Alkaline Phosphatase↗

PubMed1998

Tumor expression studies indicate that HEM-1 is unlikely to be the active factor in oncogenic osteomalacia.

HEM-1 was isolated as a putative factor responsible for oncogenic osteomalacia by Kumar et al. (Proc Assoc Am Phys 107:296-305; 1995). The cDNA was identified on the basis of PTH-like immunoreactivity; however, no studies have been reported of the expression of HEM-1 mRNA in oncogenic osteomalacia tumors. In this study, expression of HEM-1 mRNA was investigated in two oncogenic osteomalacia tumors and in a series of normal tissues. An HEM-1 PCR product was amplified from a cDNA library from one of the tumors, with six base changes identified, as compared with the published sequence. No expression was detected, however, in the oncogenic osteomalacia tumors either by Northern blot analysis or by reverse transcriptase PCR. This indicates that, although a region of HEM-1 sequence is present in the tumor cell cDNA library, any HEM-1 expression must be at very low levels. It is unlikely, therefore, that the HEM-1 product is the active factor responsible for oncogenic osteomalacia. In the normal tissues examined, human placenta, fibroblasts, parathyroid gland, liver, fetal bone, and rat kidney cortex, HEM-1 mRNA was not detected, suggesting that it does not have a physiological role in these tissues.

Adenocarcinoma↗

PubMed1983

Parathyroid hormone response to hypocalcemia in hemodialysis patients with osteomalacia.

The parathyroid hormone response to hypocalcemia was investigated in hemodialysis patients with osteomalacia and compared to those with osteitis fibrosa. Hypocalcemia was induced during hemodialysis by employing a dialysate devoid of calcium. Patients with osteomalacia had a blunted maximum amino terminal parathyroid hormone response (+/- SD) (0.39 +/- 0.33 vs. 0.87 +/- 0.53 ng/ml, P less than 0.05) and maximum carboxy terminal parathyroid hormone response (+/- SD) (0.36 +/- 0.20 vs. 0.84 +/- 0.47, P less than 0.02) to hypocalcemia. The decline in plasma calcium was greater in patients with osteomalacia at 90 (P less than 0.05), 120 (P less than 0.01), and 150 min (P less than 0.01). In osteomalacia patients the surface density of histologically detectable trabecular bone aluminum correlated directly with the percent relative osteoid volume (P less than 0.005) and inversely with the maximum amino terminal parathyroid hormone response to hypocalcemia (P less than 0.025). These results suggest that hemodialysis patients with osteomalacia have diminished secretion of parathyroid hormone and a decreased ability to restore plasma calcium homeostasis during hypocalcemia.

Bone and Bones↗

PubMed2001

Oncogenic osteomalacia associated with mesenchymal tumour detected by indium-111 octreotide scintigraphy.

In a 40-year-old man who had suffered from vague and generalized bone pains for 7 years due to oncogenic osteomalacia, the causative tumour was finally detected by Indium-111 octreotide scintigraphy. Some characteristics of the tumour associated with oncogenic osteomalacia, such as its size, growth rate, location and origin, often make the diagnosis difficult. However, the recent discovery of somatostatin receptors in mesenchymal tumours, which are the most common cause of oncogenic osteomalacia, has raised the possibility of early detection of this devastating disorder. Here, we report that radiolabelled octreotide scintigraphy has a potential role as a diagnostic tool in oncogenic osteomalacia. However, the exact role of somatostatin receptors in tumours associated with oncogenic osteomalacia still remains elusive.

Adult↗

PubMed1986

Renal hypophosphatemic osteomalacia unmasked by hyperthyroidism.

A case of renal hypophosphatemic osteomalacia (RHO) that was unmasked by hyperthyroidism is presented. The patient presented at age 64 with pathologic leg fractures. There was no family history of osteomalacia or rickets. Initial evaluation revealed hyperthyroidism, which was treated with radioactive iodine. Despite control of thyroid function, the patient had recurrent pathologic fractures. Further evaluation revealed histologically proven osteomalacia and the biochemical findings of RHO: elevated serum alkaline phosphatase, decreased serum phosphate and tubular resorption of phosphate, and normal serum calcium, parathyroid hormone, and vitamin D levels. Other causes of osteomalacia were excluded. Treatment with phosphate and calcitriol reversed the osteomalacia. This case demonstrates that hyperthyroidism, and possibly other illnesses that affect vitamin D or bone metabolism, may unmask metabolic bone disease and that physicians should be alert for the subtle clinical and biochemical indicators of unrecognized metabolic bone disease in adults.

Bone and Bones↗

PubMed2002

New insights into phosphate homeostasis: fibroblast growth factor 23 and frizzled-related protein-4 are phosphaturic factors derived from tumors associated with osteomalacia.

PURPOSE OF REVIEW: Studies of patients with tumors associated with osteomalacia (tumor-induced osteomalacia), X-linked hypophosphatemia (XLH) and autosomal-dominant hypophosphatemic rickets have provided important new insights into the identity and mechanisms of action of factors that play a role in controlling renal phosphate excretion and serum phosphate concentrations. In the present review I discuss how these disorders may be mechanistically related to one another. RECENT FINDINGS: Patients (or mice) with these disorders manifest rickets as a result of excessive urinary phosphate losses. Tumors associated with osteomalacia elaborate factors ('phosphatonins') that increase renal phosphate excretion and reduce serum phosphate concentrations. These factors include fibroblast growth factor (FGF) 23 and frizzled-related protein-4. Mice with XLH (Hyp) elaborate a circulating factor that induces changes in mineral metabolism similar to those in patients with tumor-induced osteomalacia. In mice and humans with XLH, a mutant enzyme, phex/PHEX, cannot degrade the phosphaturic factor. Patients with autosomal-dominant hypophosphatemic rickets produce a mutant FGF 23 that is resistant to proteolytic degradation. Excessive FGF 23 activity is associated with increased renal phosphate excretion and hypophosphatemia. SUMMARY: In tumor-induced osteomalacia, excessive production of factors such as FGF 23 and frizzled-related protein-4 is associated with inability of endogenous proteolytic enzymes to degrade these individual substances, with resultant hyperphosphaturia, hypophosphatemia, and rickets. In XLH, mutant PHEX/phex (phosphate-regulating gene with homology to endopeptidases located on the X-chromosome) activity prevents degradation of a phosphaturic factor. In autosomal-dominant hypophosphatemic rickets, a mutant form of FGF 23 that is resistant to proteolytic degradation causes increased renal phosphate losses and hypophosphatemia.

Animals↗

PubMed1992

A patient with osteomalacia as single presenting symptom of gluten-sensitive enteropathy.

A 59-year-old male patient presented with invalidating osteomalacia of 2.5 years' duration. The osteomalacia was caused by severe malabsorption due to gluten-sensitive enteropathy (GSE). There were no other signs or symptoms of GSE in this patient. Clinical presentation with monosymptomatic osteomalacia is very unusual. It seems that patients with GSE who undergo little exposure to the sun are at particular risk of developing overt osteomalacia. Unrecognized GSE should always be considered in the differential diagnosis of osteomalacia.

Celiac Disease↗

PubMed1970

Secondary hyperparathyroidism in osteomalacia.

Twenty-one patients with histologically proved osteomalacia from various causes were investigated for biochemical and radiological evidence of osteomalacia and secondary hyperparathyroidism. Among the 15 who maintained a normal serum calcium, seven had a raised phosphate excretion index, seven had a raised serum alkaline phosphatase, and six had phalangeal erosions. On the other hand, six patients had a subnormal serum calcium; of these, none showed a raised phosphate excretion index, one had a raised serum alkaline phosphatase, and one had erosions. The phosphate excretion index and the alkaline phosphatase were strongly correlated (r = +0.84). It is concluded that this absence of manifest secondary hyperparathyroidism in some patients with osteomalacia is due to failure of an increase in the release of parathyroid hormone. Measurement of phosphaturia does not appear to be a useful means of detecting osteomalacia. Subsequently, the 24-hour (stable) strontium space measurement was found to be the most sensitive single biochemical screening test for osteomalacia.

Adult↗

PubMed1977

25-Hydroxycholecalciferol absorption in steatorrhoea and postgastrectomy osteomalacia.

Post-absorption levels of 25-hydroxy vitamin D (25-OHD) after oral administration of 25-hydroxycholecalciferol (25-OHD3) were measured in 11 subjects. Five had presented with steatorrhoea of various causes while six had post-gastrectomy osteomalacia. Post-absorption levels of 25-OHD were low in four of the patients with steatorrhoea but normal in five of those with post-gastrectomy osteomalacia. There was a significant inverse correlation between peak post-absorption 25-OHD levels and faecal fat excretion. All patients with active post-gastrectomy osteomalacia had subnormal baseline plasma 25-OHD levels, which indicates that the condition is due to a deficiency of vitamin D. Only two of the patients with osteomalacia had estimated dietary vitamin D intakes ofer 1-75 microng/day. These findings suggest that an oral 25-OHD absorption test may be a valuable measure of small intestinal function and that poor dietary vitamin D intake rather than impaired absorption of the vitamin may be the major cause of post-gastrectomy osteomalacia.

Adult↗

PubMed1978

Clinical, biochemical, and histological studies of osteomalacia, osteoporosis, and parathyroid function in chronic liver disease.

Twenty of 32 patients with either chronic cholestatic or hepatocellular liver disease had bone pain or recent fractures. On bone biopsy five patients had normal bone, 15 had osteomalacia, five had osteoporosis, and seven had a combination of osteomalacia and osteoporosis. In the presence of osteoporosis, osteomalacia was minimal or absent. There was no biochemical, radiological, or histological evidence of excess parathyroid activity. No significant correlations were demonstrated between the plasma and urinary biochemical findings and the presence of either osteoporosis or osteomalacia and bone biopsy was essential for correct diagnosis. There was no statistical relationship between low serum 25-hydroxy vitamin D values and the presence of osteomalacia. Bone disease was not prevented by regular intramuscular vitamin D2, although biochemical changes were improved. Drugs such as corticosteroids and cholestyramine may be important aetiological factors in hepatic osteodystrophy.

Adult↗

PubMed1979

Role of nutrition in the development of osteomalacia in the elderly.

A dietary survey has been carried out of elderly people with osteomalacia. The commonest type of osteomalacia was that associated with partial gastrectomy. Although a dietary deficiency of vitamin D has been suggested as a cause of the osteomalacia the intake of this substance was not significantly different from that in controls to explain the development of the disease. It was found, however, that patients with osteomalacia went outside much less than controls and given the contribution of sunlight to meeting vitamin D requirements it is suggested that further consideration should be given to this factor in the aetiology of post-gastrectomy osteomalacia.

Age Factors↗

PubMed1977

Osteomalacia due to 1alpha,25-dihydroxycholecalciferol deficiency. Association with a giant cell tumor of bone.

Oncogenic osteomalacia is a syndrome in which unexplained osteomalacia remits after resection of a coexisting mesenchymal tumor. We have investigated the mechanism by which a giant cell tumor of bone caused biopsy-proved osteomalacia in a 42-yr-old woman. The biochemical abnormalities were: hypophosphatemia; decreased renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate; negative calcium and phosphorus balance; hyperaminoaciduria; and subnormal calcemic response to exogenously administered parathyroid hormone. Malabsorption, hypophosphatasia, fluorosis, and acidosis were excluded as causes of the osteomalacia. Serum 25-hydroxycholecalciferol was normal (27+/-1 ng/ml). However, the serum concentration of 1alpha,25-dihydroxycholecalciferol was low (1.6+/-0.1 ng/100 ml). Oral administration of physiological amounts of 1alpha,25-dihydroxycholecalciferol resulted in resolution of the biochemical abnormalities of the syndrome and healing of the bone pathology. We suggest that tumor-induced inhibition of 1alpha,25-dihydroxycholecalciferol synthesis caused the osteomalacia. The causal role of the tumor was proved by demonstrating that resection was accompanied by roentgenographic evidence of bone healing and maintenance of normal serum phosphorus; renal tubular maximum for the reabsorption of phosphate; calcium and phosphorus balance; aminoaciduria; and calcemic response to exogenous parathyroid hormone.

Adult↗