Osteoclastogenesis inhibitory factor exhibits hypocalcemic effects in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy

Osteoclastogenesis inhibitory factor (OCIF) is a novel secreted protein that inhibits osteoclastogenesis both in vitro and in vivo. In this study, we examined the effects of OCIF on serum calcium (Ca) concentrations in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy. In normal mice, a single intraperitoneal injection of OCIF reduced serum Ca levels in a dose-dependent manner. Significant decrease in serum Ca (by 1.6 ± 0.3 mg/dL, n = 5) was observed 2 h after the injection of OCIF at 20 mg/kg and the hypocalcemic effect continued for up to 12 h. Serum phosphate (Pi) concentrations also decreased in response to OCIF. Urinary excretion of Ca, Pi, and creatinine did not change significantly after injection of OCIF or vehicle. In hypercalcemic, tumor-bearing nude mice, a single intraperitoneal injection of OCIF at 20 mg/kg resulted in a dramatic decrease in serum Ca (maximal decrease 2.8 ± 0.37 mg/dL, n = 11), which continued for up to 24 h. The results suggest that OCIF decreased serum Ca through its inhibitory effect on bone resorption. Furthermore, it is suggested that OCIF has therapeutic potential for the treatment of hypercalcemic conditions such as malignancy-associated hypercalcemia.     

A model for malignancy-associated humoral hypercalcemia

Summary Tumor tissue from a patient with squamous cell carcinoma of the lung and hypercalcemia has been serially implanted into athymic mice. Tumor-bearing mice develop cachexia, hypercalcemia without bone metastases, hypophosphatemia, increased urinary cyclic adenosine monophosphate (cAMP) to creatinine ratio, and undetectable human immunoreactive parathyroid hormone levels. Radiographs of spines in the tumor-bearing mice demonstrate demineralization, suggesting skeletal resorption as the source of the hypercalcemia. Within 4–8 hours following tumor removal, hypercalcemia is reversed, suggesting that a relatively short-acting humoral substance is responsible for the hypercalcemia. The animals gain weight and become essentially normal within 4 days following tumor removal. The studies demonstrate that this animal model is similar in many aspects to human malignancy-associated humoral hypercalcemia (MAHH) and can provide a useful tool for further investigation of the pathogenesis and treatment of this syndrome.     

Nasal human calcitonin for tumor-induced hypercalcemia

Summary We treated four hypercalcemic cancer patients by nasal hCT, 3×2 mg daily, which has been reported to be active in Paget's disease at lower doses. Only one patient became normocalcemic and mean (± SEM) calcium levels fell from 11.6±0.2 mg/dl before therapy to 10.7±0.6 mg/dl 2–3 days after starting hCT. The tolerance was excellent but, because of insufficient efficacy, we do not recommend this form of therapy for cancer hypercalcemia.     

Genetic Aspects of Congenital Urologic Anomalies

Congenital malformations can be regarded as the result of abnormal foetal development. From a genetic point of view, most congenital malformations are complex genetic disorders. Both genes and environmental factors are important, but their relative impact differs in different malformations as well as individually. Malformations can thus arise through faults in different pathways, resulting in subgroups with different needs for treatment and follow-up.Most malformations are sporadic and isolated, but if families or relatives are affected, a genetic background is likely. The estimation of the genetic background is based on whether there are affected relatives or families with a Mendelian inheritance, concordance among twins, and association with other malformations or chromosomal aberrations.In paediatric urology, the genetic influence is especially high in vesicoureteral reflux and hypospadias, with a relative risk of 50 and 20, respectively, among siblings. Genes encoding for these malformations have been identified, especially for hypospadias. Bladder exstrophy is a rare malformation (1:35 000), but the risk for siblings is around 1%, resulting in a comparatively high relative risk. In cryptorchidism, there is an increased incidence among first-degree male relatives. In a small number of cases, there is a monogenetic explanation with mutations in the insulin-like 3 (Leydig cell; INSL3) gene and the corresponding receptor. In posterior urethral valves and congenital hydronephrosis, only a few familial cases have been described, indicating a low genetic influence. Improved knowledge of the molecular background of malformations allows for better information and counselling of affected patients and families.     

Cis-platinum treatment for malignancy-associated humoral hypercalcemia in an athymic mouse model

Summary We have established a model for malignancy-associated humoral hypercalcemia (MAHH) in athymic mice, utilizing a human squamous cell lung carcinoma. In the present studies, we evaluated cis-platinum (DDP), a cytotoxic agent known to produce hypomagnesemia, and occasionally hypocalcemia, in the treatment of MAHH. Upon development of significant hypercalcemia, defined as serum calcium (Ca)⩾11.5 mg/dl, tumor-bearing mice received either normal saline (NS) alone (1.5 ml/day, i.p.), or NS+DDP. The DDP was given as a single dose of 6 μg/g body weight i.p. Serum Ca was determined on day 6 in surviving mice (6 of 10 survived in the NS-alone group; 7 of 10 survived in the NS+DDP group). Serum Ca (mean±SE) decreased from 14.3±0.46 to a nadir of 12.7±0.33 mg/dl in the NS-alone group, and from 13.5±0.46 to a nadir of 10.4±0.48 mg/dl in the NS+DDP group. Nadir serum Ca levels were significantly lower in the NS+DDP group (P=0.003). Three of 7 surviving NS+DDP mice achieved normocalcemia, whereas none of the NS-alone animals became normocalcemic. Tumor volumes increased in all animals. There was no change in the serum Ca in 5 tumor-free mice treated with NS+DDP. There were no significant differences in serum magnesium levels among groups of control mice, tumor-free mice treated with NS+DDP, tumor-bearing mice treated with NS+DDP, and tumor-bearing mice treated with NS-alone. We conclude that DDP is an effective agent for the treatment of MAHH, through a mechanism distinct from its antitumor cytotoxic effect and its potential to produce hypomagnesemia.     

The effects of dichloromethylene diphosphonate on hypercalcemia and other parameters of the humoral hypercalcemia of malignancy in the rat leydig cell tumor

Summary There is a high frequency of Leydig cell tumors associated with hypercalcemia in the aged Fischer 344 rat. We studied a transplantable tumor cell line (Rice D-6) which is associated with hypercalcemia, hypercalciuria, hypophosphatemia, renal phosphate wasting, increased urinary cyclic adenosine monophosphate (AMP) excretion, absence of bone metastases, increased osteoclastic bone resorption, and suppressed immunoreactive parathyroid hormone (iPTH) concentrations. We examined the ability of dichloromethylene diphosphonate (Cl₂MDP) to lower serum calcium and decrease the parameters of increased bone resorption. We used this drug also as a pharmacologic tool to determine the relationship of hypercalcemia and increased bone resorption to the abnormalities in renal tubular function associated with the humoral hypercalcemia of malignancy. Daily administration of Cl₂MDP before development of hypercalcemia, in doses from 2.5–40 mg/kg body weight subcutaneously, delayed and suppressed both the hypercalcemia and hypercalciuria. There was an increase in bone mass and decrease in both osteoclast number and activity compared with bones from untreated tumor-bearing animals. The urinary hydroxyproline excretion in treated animals declined towards the normal range. There were no significant effects on serum phosphorus, urine phosphorus, or urine cyclic AMP excretion. These data suggest that Cl₂MDP reverses the increased bone resorption that occurs in the humoral hypercalcemia of malignancy, and confirms that diphosphonates are effective agents in the prevention and treatment of increased bone resorption associated with malignant disease. They also suggest that renal phosphate wasting and increased urinary cyclic AMP excretion are not directly related to the hypercalcemia.     

Small cell carcinoma of the prostate with hypercalcemia

We present a case of small cell prostate carcinoma with hypercalcemia in a 75-year-old man. He was diagnosed as having stage T3bN1M0 adenocarcinoma of the prostate. His serum prostate-specific antigen level was reduced to below the normal range after a combination treatment of a luteinizing hormone-releasing hormone agonist and flutamide for prostate carcinoma. He subsequently experienced increasing fatigue, poor appetite, short time loss of consciousness and pain in his lower abdomen. His serum calcium level and carcinoembryonic antigen were increased. He died 5 months from the start of treatment. The autopsy revealed small cell carcinoma of the prostate and multiple metastasis of the lung, liver, pancreas, lymph nodes and spine.     

Idiopathic infantile hypercalcemia and renal involvement

Idiopathic infantile hypercalcemia is recognized as a rare cause of infantile hypercalcemia. Its renal consequences include nephrocalcinosis with distal tubular dysfunction, nephrolithiasis, and finally renal failure. Herein we report the case of a two-month-old infant presenting with idiopathic infantile hypercalcemia complicated with distal renal tubular acidosis (RTA) and nephrocalcinosis. Despite correction of acidosis and dehydration, the persistant hypercalcemia could only be ameliorated with calcitonin treatment. Early diagnosis and appropriate treatment is life-saving in such cases.     

Cloacogenic anal carcinoma presenting with humoral hypercalcemia: Report of a case

We present herein the case of a 60-year-old man found to have a rare type of cloacogenic anal carcinoma. The disease was advanced and aggressive with local invasion to the prostate as well as distant lymph node metastases to the neck and paraaortic region on presentation. Therefore, a palliative abdominoperineal resection was performed, 10 weeks following which the patient developed humoral hypercalcemia. Despite treatment with hydration, furosemide, steroids, and calcitonin, serum calcium continued to rise and the patient died on the 95th postoperative day. Laboratory findings revealed a decreased parathyroid hormone (PTH) level and marked elevation of parathyroid hormone-related protein (PTHRP). The detection of the PTHRP in the tumor extract and the positive immunohistochemical staining for this in the tumor cells suggested that the humoral hypercalcemia was definitely caused by its associated tumor production. Although hypercalcemia is not an uncommon complication of solid cancers in their late stage, only three other cases of rectal cancer with hypercalcemia have ever been reported. To our knowledge, this is the first documentation of cloacogenic anal carcinoma accompanied by PTHRP-induced severe humoral hypercalcemia.     

Effect of salmon calcitonin and etidronate on hypercalcemia of malignancy

Summary Hypercalcemia of malignancy is a commonly encountered serious clinical problem that often requires aggressive therapy. In order to combine the rapid hypocalcemic effects of calcitonin with the more delayed effect of a bisphosphonate, we administered etidronate, 7.5 mg/kg/day intravenously and salmon calcitonin, 100 IU subcutaneously, every 12 hours for 3 days in 9 patients with hypercalcemia associated with malignancy. The mean serum calcium concentration fell from 3.33±0.1 mmol/liter (mean±SEM) to 2.88±0.1 mmol/liter within 24 hours (P<0.001). All patients had a fall in the serum calcium concentration of >0.5 mmol/liter and it returned to normal in 7 of the 9 patients. We conclude that the combination of salmon calcitonin with etidronate more effectively lowers the serum calcium concentration in patients with hypercalcemia of malignancy then the use of either agent alone.     

Congenital mesoblastic nephroma associated with polyhydramnios and hypercalcemia

Congenital mesoblastic nephroma (CMN) can present with atypical clinical and imaging findings. A premature male neonate was born to an 18-year-old woman after 33 weeks’ gestation, which was complicated by polyhydramnios and placenta abruptio. A right abdominal mass was diagnosed antenatally. From the 1st day of life, the newborn had hypercalcemia with initially normal parathormone levels and polyuria for the first hours of life and normal urine output afterwards. Ultrasonographic study and magnetic resonance imaging of the abdomen showed at the upper pole of the right kidney a heterogeneous, solid, poorly defined mass, partially surrounded by a subcapsular fluid collection mimicking malignant rhabdoid tumor of the kidney. Surgical resection revealed a CMN of mixed, classic, and in areas, cellular type. One year after the resection, the patient is asymptomatic and normocalcemic. In conclusion, CMN may present with atypical clinical and imaging findings, necessitating an extensive work-up in order to exclude highly malignant renal tumors of the neonatal period. Received: 12 December 2000 / Revised: 1 May 2001 / Accepted: 9 October 2001     

In vitro bone resorption activity produced by a hypercalcemic adenocarcinoma tumor line (CAC-8) in nude mice

Summary Tumor extracts and conditioned tissue culture media from a canine adenocarcinoma tumor line (CAC-8) propagated in nude mice significantly increasedin vitro bone resorption in neonatal mouse calvaria as measured by release of previously incorporated⁴⁵Ca.In vitro bone resorption activity was induced in a dose-dependent manner, was not suppressible by indomethacin, and was heat- and acid-stable. Gel exclusion chromatography demonstrated peak bone resorbing activity at a relative molecular mass of approximately 28,000. The parathyroid hormone (PTH) antagonist (^8,18norleucine,³⁴tyrosine) bovine PTH (3–34) amide did not inhibit CAC 8-stimulated or (1–34) bPTH-induced bone resorption. There was an increased number of tartrate-resistant, acid phosphatase-positive cells in calvariae exposed to CAC-8 extract. Ultrastructural evaluation of calvaria revealed hypertrophy and maturation of osteoclasts in calvaria exposed to CAC-8 extract. The maturation effects included close contact to bone surfaces and the presence of clear zones and ruffled borders in osteoclasts. Similar structures were observed infrequently in osteoclasts of control calvaria. These data demonstrate that the tumor line (CAC-8) contained activity capable of stimulatingin vitro bone resorption by increasing osteoclast numbers and the activity of existing osteoclasts.     

Persistent hypercalcemia after neck exploration —An analysis of 34 cases

Summary A retrospective analysis of 34 patients undergoing 45 re-explorations for persistent hypercalcemia is presented. Thirteen out of the 20 enlarged parathyroid glands were found at reoperation to be normally located, indicating that the initial exploration had been incomplete. A follow-up study of the reoperated patients showed that 25 (74%) were normocalcaemic. Three patients had permanent unilateral recurrent laryngeal nerve damage and 2 patients required calcium and/or vitamin D therapy. Ultrasonography was effective in the diagnosis and localisation of residual parathyroid adenoma in patients with persistent postoperative hyperparathyroidism.     

The Results of Metal-On-Metal Hip Resurfacing in Patients Under 30 Years of Age

Degenerative hip conditions most commonly affect older patients. However, many cases occur in younger patients. Total hip arthroplasty is the conventional approach; however, hip resurfacing is a viable option. Fifty-three metal-on-metal resurfacings in 46 patients under age 30 were performed. Patients had a variety of etiologies, and were followed clinically and radiographically with mean follow-up of 98.2 months. Clinical scores and x-rays were compared pre-operatively and post-operatively. The last follow-up SF-12 and UCLA scores significantly improved post-operatively (P < 0.0001). Range of motion scores also improved (P < 0.001), and the mean Harris Hip Score was 88. There were 6 revisions. The Kaplan–Meier survivorship estimate at 8 years was 95%. Metal-on-metal hip resurfacing appears to be an effective procedure for younger patients. Longer-term data are needed for confirmation.     

Familial hypercalcemia and hypercalciuria: no mutations in the Ca2+-sensing receptor gene

A 6-year-old boy presented with persistent hypercalcemia, hypercalciuria and nephrocalcinosis from early infancy. His 40-year-old father also had hypercalcemia and hypercalciuria. In both individuals serum values of intact parathyroid hormone (PTH) were repeatedly normal. Although these findings suggest a functional abnormality of the calcium-sensing receptor (CaR), no mutations in coding regions of the CaR gene could be demonstrated. Received: 2 January 2001 / Revised: 2 May 2001 / Accepted: 2 May 2001     

Treatment of severe hypercalcemia with peritoneal dialysis in an infant with end-stage renal disease

Recurrent and unusually severe hypercalcemia was observed in an infant undergoing continuous cyling peritoneal dialysis and receiving oral calcitriol and calcium carbonate. Rapid correction was achieved with peritoneal dialysis using a calcium-free dialysis solution.     

Familial occurrence of idiopathic infantile hypercalcemia

Idiopathic infantile hypercalcemia (IIH) is a rare cause of hypercalcemia in the 1st year of life and was initially considered part of a spectrum encompassing vitamin D intoxication, Williams syndrome, and idiopathic hypercalcemia. Identification of the gene for Williams syndrome now allows a clear separation of IIH from Williams syndrome. The inheritance and pathogenesis of IIH remains largely unknown, with only sporadic cases reported to date. This report describes a family with two siblings with IIH. The pedigree is consistent with autosomal recessive inheritance, but more complex inheritance is suggested by the occurrence of hypercalciuria in a number of family members. Although one affected patient demonstrated elevated 1,25-dihydroxyvitamin D₃ levels, no conclusions regarding the pathogenesis of this condition could be drawn. Received: 9 September 1998 / Revised: 4 January 1999 / Accepted: 5 January 1999     

Mechanism of induction of hypercalcemia and hyperphosphatemia by lead acetate in the rat

Summary The present study is an investigation of the mechanism of hypercalcemia and hyperphosphatemia induced by the intravenous injection of lead acetate (Pb-Ac). A total of 118 male rats were injected with 30 mg/kg of Pb-Ac, or with 16.5 mg/kg of sodium acetate as the control. The levels of serum calcium, phosphorus and lead were then determined at various time periods after the injections. Serum calcium and phosphorus levels increased with time after Pb-Ac injection and the maximum values of calcium (17 mg%) were found after 1 h and of phosphorus (13.5 mg%) after 30 min. Both calcium and phosphorus levels reverted to the normal range after 12 h. The maximum net rates of increase of calcium and phosphorus were found immediately after Pb-Ac injection. At that time, deposition of lead at the calcifying sites of bone and incisor dentin was demonstrated by a histochemical examination. In other experiments the changes in the calcium and phosphorus contents in the medium after shaking bone powder in serum with Pb-Ac in an in vitro system were studied. It was confirmed that the calcium and phosphorus were displaced from the bone mineral, the extent of the displacement being correlated with the concentration of the Pb-Ac added to the medium, and that these displacements were very rapid reactions. These results suggest that hypercalcemia and hyperphosphatemia following Pb-Ac injection results from a direct action of lead on the bone mineral.     

Canine lymphosarcoma: A model for study of the hypercalcemia of cancer

Summary Lymphosarcoma of domestic dogs is often accompanied by hypercalcemia. We have carried out studies to determine the usefulness of this common canine neoplasm as a model for paraneoplastic hypercalcemia. The study population consisted of 27 healthy control dogs, 13 with hypercalcemic lymphosarcoma, and 28 normocalcemic dogs with lymphosarcoma. Studies included measurement of circulating calcium, phosphorus, creatinine, immunoreactive parathyroid hormone (iPTH) and prostaglandin E₂ (iPGE₂) concentrations, and determination of in vitro bone-resorbing activity in supernatant culture media from normal and neoplastic lymphoid tissue. Hypercalcemia was severe in the affected group (mean ± SE, 14.9±0.5 mg/dl, normals 10.1±0.1 mg/dl) and associated with decreased renal function (serum creatinine 2.0±0.4 mg/dl, normal 0.8±0.1 mg/dl,P<0.001). Radiographs and autopsies showed no bone destruction. Despite renal insufficiency, hypercalcemic dogs had subnormal serum iPTH concentrations (12±1 ngEq/ml, normals 37±6 ngEq/ml,P<0.05). Creatinine and iPTH were normal in the normocalcemic tumor-bearing dogs. When antitumor therapy lowered serum calcium to normal or below in 5 hypercalcemic dogs, iPTH rose markedly in all while renal function improved. Plasma iPGE₂ levels did not differ among the groups, nor did high-dose oral aspirin or indomethacin treatment lower elevated serum calcium (two dogs). Culture media from normal lymphoid tissue and control culture media had no effect on release of⁴⁵Ca from prelabeled fetal mouse forelimb bones, but media from tumor tissue increased⁴⁵Ca release. However, correlation of serum calcium with in vitro bone-resorbing activity was poor. We conclude that (a) the hypercalcemia of canine lymphosarcoma is mediated not by bone metastases or “ectopic” secretion of PTH, but by other bone-resorbing factors secreted by the tumors; and (b) canine lymphosarcoma may be a valuable experimental model for study of some human paraneoplastic hypercalcemias. Present address: Mackintosh Veterinary Clinic, 401 South First Street, Yakima, WA 98907, USA.     

Humoral hypercalcemia due to an occult renal adenoma

Humoral hypercalcemia refers to the elevated blood calcium levels caused by neoplasms which release a bone resorptive substance into the circulation. Previously reported infants with malignant and benign solid tumors causing humoral hypercalcemia have presented with large abdominal masses. The case we describe, a hypercalcemic infant due to an occult parathyroid hormone-related protein-containing metanephric adenoma of the kidney, shows that radionuclide bone scanning can be a useful test to identify humoral hypercalcemia. Humoral hypercalcemia stemming from a soft tissue neoplasm should be ruled out, even in the absence of clinical signs of a tumor, if bone scans show generalized uptake in the absence of hypervitaminosis D or radiological signs of bone lesions, and serum parathyroid hormone is low. Received July 1, 1996; received in revised form and accepted December 10, 1996