Vitamin D-resistant Osteomalacia Research Articles

The enthesopathy of vitamin D-resistant osteomalacia in adults

A case of an adult patient with vitamin D-resistant osteomalacia or X-linked hypophosphatemic osteomalacia (XLH) with diffuse calcification of entheses is reported. XLH is the most frequent cause of rickets in developed countries. It is characterized by an impaired renal transport of the phosphate and mutation of PFEX (phosphate regulating gene, with homologies to endopeptidase on the X-chromosome). In childhood, the classic clinical presentation includes short stature and bow leg. While at this age the main radiographic features are characterised by rickets, in adult life they are dominated by a generalised calcific enthesopathy. Concerning the pathogenesis of the enthesopathic lesions of XLH, no convincing hypothesis has yet been made. As in our patient, the extension and the severity of enthesopathy seems not related to the severity of the biochemical changes nor to the treatment with calcitriol. The calcified enthesopathy is an integral part of XLH and it is possible that it is found in adult because many years are necessary to produce it.

Simultaneous, Bilateral Pathological Displaced Intracapsular Hip Fractures Occurring Spontaneously Secondary to Osteomalacia of Hypomagnesemic Origin: A Case Report and Review of the Literature.

Spontaneous fractures involving both of the femoral necks simultaneously are exceedingly rare events. We report a case of an elderly female who presented after breaking both femoral necks following a trivial fall, initially diagnosed as age-related osteoporosis. Both the hips were treated by hemiarthroplasty. The diagnosis was revised to vitamin D-resistant osteomalacia secondary to hypomagnesemia after histopathological confirmation and further investigations. We examine the different etiological factors and mechanisms operating in the causation of this rare injury and explore the possible role of magnesium in the pathogenesis of osteomalacia. Fractures may remain occult until late, leading to increased morbidity and mortality. The value of an early MRI is recapitulated, with emphasis placed on prevention and early fixation.

Adult-onset vitamin D-resistant osteomalacia. A case with seventeen-year follow-up.

Adult-onset vitamin D-resistant osteomalacia. A case with seventeen-year follow-up.

Tumor-Induced Osteomalacia and Rickets

Tumor-induced osteomalacia is a clinicopathological entity in which vitamin D-resistant osteomalacia or rickets occurs in association with a tumor. A total of 72 cases (three current, 69 from review of literature) has been reported to date. Men and women are equally affected. The majority are adults over 30 years old who exhibit progressive lower leg and back pain. Forty bone and 31 soft-tissue tumors were responsible for this syndrome; two-thirds occurred in the extremities. Chemical findings are typical: low serum phosphorus, normal serum calcium, and elevated alkaline phosphatase. Serum levels of 1,25-dihydroxyvitamin D were low or undetectable. Histologically, more than a third were classified as vascular tumors, and half of these cases were hemangiopericytomas that were distributed equally between bone and soft tissues. Other common diagnoses included nonossifying fibromas, "mesenchymal" and giant-cell tumor variants. Features common to all tumors were prominent vascularity, and giant and primitive stromal cells. Only 10 were histologically malignant. Ultrastructural studies have not shown any secretory granules suggestive of a hormone-secreting tumor. It is clear, however, that the tumor is responsible for the osteomalacia because the complete removal generally results in a dramatic reversal of all symptoms and signs.

Renal osteodystrophy: some new questions on an old disorder.

The two major lesions of renal osteodystrophy are osteitis fibrosa cystica (OFC) and osteomalacia (OM). OFC is the characteristic bone lesion of uremic hyperparathyroidism. Although renal failure causes predictable parathyroid hyperplasia, the precise pathogenetic mechanism is still not defined. The "hyperphosphatemia-hypocalcemia-parathyroid hormone (PTH) hypersecretion" sequence of events is no longer an adequate model for the pathogenesis of uremic hyperparathyroidism. Other abnormalities associated with uremia include reduced 1,25-dihydroxyvitamin D (1,25D) synthesis, changes in intracellular phosphorus content or transcellular phosphate fluxes, or alteration in PTH metabolism, eg, change in set-point for PTH secretion. Each abnormality interacts with others and contributes to PTH hypersecretion, but none can completely account for the development and persistence of hyperparathyroidism in renal failure. The possibility that uremia may directly cause parathyroid hyperplasia remains open. It is also possible that factor(s) that initiate hyperparathyroidism may turn out to be quite different from that which sustains the hyperparathyroid state. Although both vitamin D-deficient and vitamin D-resistant OM may develop in patients with renal failure, the majority of uremic OM seen currently is "vitamin D-refractory." Although now there is persuasive evidence implicating aluminum (Al) accumulation as the major pathogenetic cause for the mineralization defect seen in this disorder, additional disturbances may play important contributory roles. Such factors would include extraskeletal effects of Al, differences in host-susceptibility to this element, the localization of Al within bone, uremia per se, and the participation of other metals and toxins. Finally, possible interactions between hyperparathyroidism and OM of uremia are speculated on.

A tumour-like bone lesion as a manifestation of vitamin D-resistant hypophosphataemic osteomalacia

In 1959 Prader et al described for the first time an association of vitamin D-resistant hypophosphataemic rickets with a giant-cell granuloma. Removal of this tumour, located in a rib, led to complete healing of the rickets. Since then such tumours, usually of mesenchymatous origin, have been found in a number of patients with rickets or osteomalacia and the condition has become known under various names such as tumour rickets, oncogenic rickets and tumour-induced hypophosphataemic rickets (or osteomalacia, when it occurs in adults) (Ryan & Reiss, 1984). This condition should be distinguished from X-linked or congenital hypophosphataemic vitamin D-resistant rickets. Marked hypophosphataemia resulting from reduced renal tubular reabsorption of phosphate is the common finding in both conditions and although there are clinical differences between them the diagnosis can sometimes be difficult. Here we describe a patient with congenital hypophosphataemic rickets and a bone lesion which had all the radiological...

Intestinal absorption of aluminium in rats: effect of sodium.

Aluminium (Al) is no longer known as a non-toxic element. Al is the cause of several dialysis-related diseases (microcytic anaemia, vitamin D-resistant osteomalacia, dialysis encephalopathy) and plays a possible role in various other disorders (Alzheimer’s disease, amyotrophic lateral sclerosis) (Flendrig et al. 1976; Alfrey et al. 1976; Wills and Savory 1983). The Al uptake from the intestine may be one of the main sources of Al in the body and, therefore, of Al toxicity, especially in renal patients on oral Al hydroxide therapy (Clarkson et al. 1972; Cam et al. 1980; Griswold et al. 1983; Randall 1983; Kaye 1983; Cannata et al. 1983a).KeywordsAmyotrophic Lateral SclerosisIntestinal AbsorptionBrown TroutAluminium HydroxideFlameless Atomic AbsorptionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

The effects of aluminum loading on the renal response to parathyroid hormone in the vitamin D-replete rat

Aluminum (Al) may cause vitamin D-resistant osteomalacia and depress the serum levels of immunoreactive parathyroid hormone (iPTH) in patients treated with maintenance dialysis and those on total parental nutrition (TPN). Both conditions have been associated with low serum levels of 1,25(OH)2-vitamin D (1,25(OH)2D). Al may inhibit PTH secretion in vitro; however, induction of hypocalcemia can enhance endogenous PTH secretion in Al-loaded dogs and TPN patients. Despite hypocalcemia and/or increased endogenous iPTH levels, Al-loaded TPN patients fail to show the expected rise in serum 1,25(OH)2D levels. Such observations suggest that Al may impair the renal response to PTH. We studied vitamin D-replete rats given Al or saline vehicle IP for 5 days. Al and control rats then received a saline infusion with an IV bolus of PTH 1-34. Urinary cyclic AMP and P excretion rose in Al and control rats by 1 hr post-PTH, without differences between the groups. Serum P and ionized Ca levels were not different between Al and control rats. In other Al and control rats, serum 1,25(OH)2D levels were measured after saline without PTH. Serum 1,25(OH)2D levels were higher in controls given PTH than in those without, but 1,25(OH)2D levels were not different between Al rats given PTH and those with none. Thus, aluminum does not affect cyclic AMP or P excretion but may impair 25(OH)D-1 alpha-hydroxylase activity in response to PTH.

Clinical and Laboratory Features of Aluminum-Related Bone Disease: Differences Between Sporadic and “Epidemic” Forms of the Syndrome

R EPORTS from the United Kingdom first described a constellation of musculoskeletal signs and symptoms in as many as 30% of dialysis patients from certain geographic areas with water aluminum levels above 75 to 100 j-tg/L1-3; the clinical features included bone pain, myopathy, multiple fractures, and encephalopathy. Bone biopsies demonstrated osteomalacia. Biochemical parameters included a tendency toward hypercalcemia, normal or only mildly elevated alkaline phosphatase levels, normal or lower than predicted serum iPTH levels, and a microcytic anemia. In the United States, such patients were uncommon, and the prevalence of vitamin D-resistant osteomalacia in patients from several dialysis units was estimated at I % to 3 % .4 Aluminum-related bone disease can also occur from the intestinal absorption of aluminum from the phosphate binders taken by these patients; this may be the most prevalent cause in the United States. 4·6 We describe the clinical and biochemical features of 40 dialysis patients with biopsy-proven and symptomatic aluminum-related bone disease, most from dialysis units using adequately treated water. In contrast to other patients with comparable durations of dialysis (asymptomatic patients and those with osteitis fibrosa), the features of

Evidence of increased parathyroid activity on discontinuation of high-aluminum dialysate in patients undergoing hemodialysis

High-aluminum dialysate exposure has been incriminated in the pathogenesis of vitamin D-resistant osteomalacia in patients undergoing long-term hemodialysis. Parathyroid-mediated osteitis fibrosa is rare in these patients. Thirteen patients undergoing long-term hemodialysis were transferred from a center (Unit A) where water used to prepare dialysate was high in aluminum (100 to 450 μg/liter) to a new center (Unit B) where dialysate was highly purified (aluminum concentration less than 10 μg/liter), and changes in calcium metabolism were studied over a 12-month period. After transfer of patients to Unit B, serum aluminum levels fell (p < 0.01), whereas serum immunoreactive parathyroid hormone levels rose (p < 0.01) over 10 months. Over this time, predialysis serum calcium levels did not alter significantly, whereas postdialysls serum calcium levels declined slightly (p < 0.05). Serum phosphate levels did not alter. Serum alkaline phosphatase levels rose progressively in Unit B (p < 0.001). Discontinuation of dialysate high in aluminum in patients undergoing long-term hemodialysis may facilitate a rise in parathyroid activity.

Accumulation of Aluminum in a Nondialyzed Uremic Child Receiving Aluminum Hydroxide

A child with renal insufficiency was treated with the oral phosphate binder aluminum hydroxide from age 6 to 31 months. The prescribed dose of elemental aluminum varied from 31 to 108 mg/kg/d. Concurrently the patient developed vitamin D-resistant osteomalacia which failed to improve with parathyroidectomy. Encephalopathy with myoclonic seizures, loss of speech, and motor impairment also occurred. Serum and bone aluminum levels were elevated at 334 micrograms/L (normal 7 +/- 3 micrograms/L) and 156 mg/kg (normal 3.3 +/- 2.9 mg/kg), respectively. This case demonstrates that aluminum may accumulate in tissue of children receiving oral aluminum hydroxide. The accumulation of aluminum may have contributed to the vitamin D-resistant osteomalacia and the encephalopathy in this patient. Children receiving aluminum-containing antacids as phosphate binders should be monitored for aluminum accumulation and signs of aluminum intoxication.

Bone histomorphometry in asymptomatic adults with hereditary hypophosphatemic vitamin D-resistant osteomalacia

Vitamin D-resistant rickets (VDRR) in adults is characterized by low serum phosphorus and osteomalacia. Despite the disappearance of rickets after the closure of epiphyses, some adults with VDRR present with symptomatic bone disease while other are asymptomatic. In order to test the presumption that asymptomatic adults no longer have active bone disease, we have compared bone histology in 10 symptom-free adults to 6 age-comparable symptomatic adults presenting with bone pain and persistent deformities. Both groups had similar low serum phosphorus and increased serum alkaline phosphatase values. Serum calcium, parathyroid hormone, and vitamin D metabolite concentrations were not different in the two groups. Histomorphometric study of bone formation and resorption was made on undecalcified sections of iliac crest bone biopsies obtained after in vivo single or dual tetracycline labeling. Bone histology revealed that both groups of patients had comparable osteomalacia, as evidenced by increased amount of osteoid tissue, prolonged mineralization lag time, and reduced bone formation rate. Despite the presence of osteomalacia, the trabecular calcified bone volume was within or above normal values in the two groups, implying a remodeling imbalance between the rates of bone resorption and formation. The data show that despite the absence of symptoms and the disappearance of rickets, adults with VDRR still have active bone disease characterized by moderate to severe osteomalacia. The normal to increased trabecular bone mass implies implies that the occurrence of painful symptoma results from factors other than trabecular osteopenia. These observations thus lead one to question the utility of active medical treatment with vitamin D and/or phosphate in asymptomatic adults with VDRR.

Vitamin D preparations: alfacalcidol (one-alpha) and others

Since we last discussed vitamin D therapy1 the synthetic vitamin D analogue 1α-hydroxyvitamin D3 has become available as alfacalcidol (One-Alpha - Leo). It is recommended for treatment of hypoparathyroidism, renal bone disease, vitamin D-dependent rickets, vitamin D-resistant hypophosphataemic rickets and osteomalacia. Peri-operative treatment is also recommended to reduce the risks of hypocalcaemia after parathyroidectomy.

A Case of Adult-Onset Vitamin-D Resistant Osteomalacia with Elevated Plasma Parathyroid Hormone Level

A sixteen-year-old girl with adult-onset vitamin-D resistant osteomalacia had an elevated plasma immunoreactive parathyroid hormone level which was readily suppressed by intravenous calcium infusion. Treatment with 300,000 units of vitamin D2 normalized the high plasma immunoreactive parathyroid hormone level as well as augmented phosphaturia. Parathyroid hormone appears to play an important role in the development of vitamin-D resistant rickets in this case.

Normophosphatemic vitamin D-resistant osteomalacia in a patient with normal calcium and fat absorption.

The clinical data, calcium metabolic studies, and histological examination of bone in a patient with severe progressive bone demineralization are discussed with respect to the etiology of the bone disease. Several features are consistent with osteomalacia: multiple pseudofractures, subperiosteal resorption, hypocalcemia, increased calcium retention after an intravenous infusion of calcium, decreased bone apposition, and increased amount of bone surface lined by osteoid. Osteoid seam width was not increased, however, and fat and calcium absorption and response to an NH4Cl load all were normal. Because vitamin D antirachitic activity was present in serum, and treatment with vitamin D and sodium fluoride did not lead to clinical improvement, this patient may have an acquired abnormality of bone cells associated with progressive skeletal demineralization and plastic deformities.

Urinary excretion of 3′,5′-AMP in syndromes considered refractory to parathyroid hormone

Earlier studies showed that parathyroid hormone increases the urinary excretion of cyclic 3′,5′-AMP in normal subjects; patients with pseudohypoparathyroidism showed little or no response. In the current investigation this response to parathyroid hormone was examined in several apparently unrelated syndromes previously characterized as resistant to the hormone in tests for phosphaturia. The disorders studied included the basal cell nevus syndrome (BCN), Gardner's syndrome (GS), vitamin D-resistant osteomalacia (DRO), and the syndrome of basal ganglia calcification (BGC). Urine was collected on two successive mornings and 180 USP units of purified bovine parathyroid hormone were infused between 9 and 9:15 a.m. on day 2. During the control day (Day 1) normal volunteers showed average excretion of 3′,5′-AMP of 3.90 nmoles/mg. creatinine (range 2.4–5.4). Baseline excretion for patients averaged 2.90 (BCN), 5.19 (GS), 5.30 (DRO), and 5.27 (BGC) nmoles of 3′,5′-AMP/mg. creatinine. Base-line excretion rates for patients with GS, DRO, and BGC were significantly greater than normal. This finding possibly reflects secondary hyperparathyroidism in DRO but remains unexplained in GS and BGC. Infusion of hormone into normal subjects caused an increase to 23.7 nmoles of 3′,5′-AMP/mg. creatinine (range 13–42). The responses to the hormone for the patient groups were 32 (BCN), 48 (GS), 56.1 (DRO), and 47.4 (BGC) nmoles of 3′,5′-AMP/mg. creatinine. These results were within the limits of normal. There were wide fluctuations in phosphate excretion from day-to-day as well as hour-to-hour in all groups. These variations obscured the phosphaturic response in the normal subjects and in patients with Gardner's syndrome, vitamin D-resistant osteomalacia and the family with calcification of the basal ganglia. The basal cell nevus syndrome showed a significant phosphaturic response to the hormone. These results confirm previous conclusions that the phosphaturic response is not sufficiently reliable to categorize a syndrome as refractory to PTH. On the other hand, the rate of excretion of 3′,5′-AMP shows less variation and the response provides more valid discrimination between normal subjects and those refractory to the hormone. Thus, the current studies show that several syndromes previously described as resistant to parathyroid hormone indeed respond normally.

Symptomatic osteomalacia secondary to clinically occult causes.

Case Reports1 June 1961SYMPTOMATIC OSTEOMALACIA SECONDARY TO CLINICALLY OCCULT CAUSESRICHARD C. POWELL, M.D., WILLIAM P. DEISS JR., M.D., F.A.C.P.RICHARD C. POWELL, M.D.Search for more papers by this author, WILLIAM P. DEISS JR., M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-54-6-1280 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThe purpose of this report is to describe two adult patients with disabling osteomalacia. The feature worthy of emphasis in each case is the negligible symptomatology referable to the organ systems believed to be the sites of the primary defects—in the first case, the gastrointestinal tract with occult steatorrhea; in the second, the kidneys with latent tubular acidosis.CASE REPORTSCase 1. A 50-year-old housewife was first seen by us in February, 1959, complaining of stiffness and generalized aching pain in her back and both lower extremities. The pain was not well localized. The onset of symptoms was insidious, and...Bibliography1. Milkman LA: Multiple spontaneous idiopathic symmetrical fractures. Amer. J. Roentgenol. 32: 622, 1934. Google Scholar2. AlbrightReifenstein FEC: The parathyroid glands and metabolic bone disease: selected studies. The Williams and Wilkins Company, Baltimore. 1948. Google Scholar3. CameronBensleyWood DGEHP: Latent steatorrhea. Ann. Intern. Med. 37: 553, 1952. LinkGoogle Scholar4. JuergensScholzWollaeger JSDAEE: Severe osteomalacia associated with occult steatorrhea due to nontropical sprue: report of five cases. Arch. Intern. Med. 98: 774, 1956. CrossrefGoogle Scholar5. Mudge GH: Clinical patterns of tubular dysfunction. Amer. J. Med. 24: 785, 1958. CrossrefMedlineGoogle Scholar6. FossPerryWood GLCBFJ: Renal tubular acidosis. Quart. J. Med. 25: 18, 1956. Google Scholar7. SchreinerSmithKyle GELHLH: Renal hyperchloremic acidosis: familial occurrence of nephrocalcinosis with hyperchloremia and low serum bicarbonate. Amer. J. Med. 15: 122, 1953. CrossrefMedlineGoogle Scholar8. AlbrightBurnettParsonReifensteinRoos FCHWECA: Osteomalacia and late rickets. Medicine 25: 399, 1946. CrossrefMedlineGoogle Scholar9. MilneStanburyThomson MDSWAE: Observations on the Fanconi syndrome and renal hyperchloraemic acidosis in the adult. Quart. J. Med. 21: 61, 1952. MedlineGoogle Scholar10. JacksonLinder WPGC: Innate functional defects of the renal tubules, with particular reference to the Fanconi syndrome: cases with retinitis pigmentosa. Quart. J. Med. 22: 133, 1953. MedlineGoogle Scholar11. JacksonDowdleLinder WPEGC: Vitamin D-resistant osteomalacia. Brit. Med. J. 1: 1269, 1958. CrossrefMedlineGoogle Scholar12. Reynolds TB: Observations on the pathogenesis of renal tubular acidosis. Amer. J. Med. 25: 503, 1958. CrossrefMedlineGoogle Scholar13. ElkintonHuthClarkBarkerSeligson JREJJKESD: Renal tubular acidosis with organic aciduria during paraldehyde ingestion: six-year study of an unusual case. Amer. J. Med. 23: 977, 1957. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Indianapolis, Indiana*Received for publication September 14, 1959.From the Department of Medicine, Indiana University School of Medicine.Requests for reprints should be addressed to Richard C. Powell, M.D., Department of Medicine, Indiana University School of Medicine, Indianapolis 7, Ind. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byDisabling osteomalacic myopathy as the only presenting feature of coeliac diseaseA patient with osteomalacia as single presenting symptom of gluten-sensitive enteropathyDas PeritoneumDie intestinale Calcium-Resorption und ihre St�rungenDie erworbenen, generalisierten OsteopathienCalcium Absorption in Health and DiseaseRecent Progress in Osteomalacia and RicketsA. ROBERT ARNSTEIN, M.D., BOY FRAME, M.D., F.A.C.P., HAROLD M. FROST, M.D.Hypocalcemia — An Unusual Metabolic Complication of Breast CancerGluten-Sensitive Enteropathy with Osteomalacia but without Steatorrhea 1 June 1961Volume 54, Issue 6Page: 1280-1289KeywordsAnemiaCalciumExcretionGastrointestinal tractKidneysLower back painStiffnessUrea Issue Published: 1 June 1961 PDF downloadLoading ...

Phosphate diabetes: A case study of osteomalacia

A case report is presented of a patient with vitamin D-resistant osteomalacia. The basic defect was considered to be a reduced renal tubular reabsorption of phosphorus with resulting hypophosphatemia. After lengthy therapy with calcium lactate and large doses of vitamin D was only partially successful, supplemental phosphorus administered orally resulted in marked improvement. Symptoms abated, calcium and phosphorus retention increased, and reossification was noted in x-ray films of the demineralized skeleton. Parathyroidectomy was performed but its contribution to the over-all results cannot be stated.