Osteocalcin and urinary hydroxyproline/creatinine ratio in the differential diagnosis of primary hyperparathyroidism and hypercalcaemia of malignancy

Osteocalcin (serum bone-Gla protein, sBGP), serum alkaline phosphatase (sAP) and urinary hydroxyproline/creatinine ratio (uOH-Prol/creatinine) have been measured in 21 patients with primary hyperparathyroidism (PHPT) and in nine patients with hypercalcaemia of malignancy (HM). A positive linear correlation between sBGP and uOH-Prol/creatinine ratio (y = 0.023 + 0.0025x; r = 0.705; p less than 0.01) and between sBGP and sAP (y = 35.6 + 2.14x; r = 0.430, p less than 0.05), have been observed in the PHPT patients. No correlation was found in the HM patients. PHPT patients have been grouped according to their uOH-Prol/creatinine ratio (group A: uOH-Prol/creatinine greater than 0.034; group B: uOH-Prol/creatinine less than or equal to 0.034). Group A presented sBGP higher than the control group (11.06 +/- 5.7 vs. 4.2 +/- 1.2 ng/ml; p less than 0.001) (mean +/- SD). Group B presented sBGP similar to the control group (4.4 +/- 1.96 ng/ml) (mean +/- SD). Group A presented serum calcium (sCa) higher than group B (3.11 +/- 0.28 vs. 2.78 +/- 0.09 mmol/l; p less than 0.01) (mean +/- SD). In HM patients uOH-Prol/creatinine ratio was elevated as compared with the control group (0.074 +/- 0.036 vs. 0.024 +/- 0.004; p less than 0.001) (mean +/- SD), but sBGP was normal or low (range: indetectable-5.1 ng/ml). The simultaneous estimations of sBGP and uOH-Prol/creatinine ratio improve the differential diagnosis between these two forms of hypercalcaemia: high uOH-Prol/creatinine ratio with concomitant high sBGP point to the presence of PHPT. Elevated uOH-Prol/creatinine ratio with normal or low sBGP suggest the existence of HM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Primary hyperparathyroidism or hypercalcaemia of malignancy?

The introduction of two-site immunometric assays measuring intact parathyroid hormone (PTH) and radioimmunoassays measuring PTH-related peptide (PTH-RP) have simplified the evaluation of patients with hypercalcaemia. We present a 63-year-old man with recurrent hypercalcaemia after surgical treatment for primary hyperparathyroidism 3 years previously. PTH measured with a mid-region radioimmunoassay gave normal values, at the same level as during his primary hyperparathyroidism. Intact PTH was, however, clearly suppressed, and he had a highly elevated level of PTH-RP. This suggested that he had humoral hypercalcaemia of malignancy. The patient died after 2 months, and at autopsy an adenocarcinoma of the pancreas with no skeletal metastases was found.     

The origin of urinary hydroxylysyl glycosides in Paget's disease of bone and in primary hyperparathyroidism.

The urinary excretion of glucosyl-galactosyl-hydroxylysine and of galactosyl-hydroxylysine were studied in Paget's disease of bone and in primary hyperparathyroidism. Both metabolites were increased in these diseases. Although glucosyl-galactosyl-hydroxylysine is not abundant in bone collagen, it is possible that a part of it originates from calcified tissue.     

Paget's disease of bone

Paget's disease of bone (PDB) is a chronic disorder characterized by focal abnormalities of bone turnover. The symptoms of PDB include bone pain, bone deformity, osteoarthritis, and an increase in risk of pathological fracture and neurological problems. PDB is the second most common metabolic bone disease in European countries, although PDB is uncommon in Japan. PDB shows geographical and ethnic clustering. Based on this, two hypotheses of etiology of PDB have been proposed. One hypothesis is that PDB results from a slow virus infection of osteoclasts with paramyxovirus. The other is that PDB is a genetic disease. The development of bisphosphonate has brought major changes to the treatment of PDB. In Japan, etidronate and calcitonin are approved by the Ministry of Health, Labour and Welfare for treating PDB. Risedronate is under development for treating PDB in Japan.     

Paget's disease of bone

ObjectivesTo review recent advance in understanding the causation and management of Paget's disease.Design and methodsWe review recent publications concerning the aetiology of the disease and the use of biochemical markers of bone turnover in diagnosis and treatment.ResultsEpidemiologic studies suggest that Paget's disease is decreasing in prevalence and severity (implying that environmental factors are important) but there is also strong evidence of a genetic predisposition particularly through the SQSTM1 gene.Genome-wide association studies have identified polymorphisms at several other loci that are associated with the disease. Plasma alkaline phosphatase activity (ALP) is widely used, but less helpful in patients with disease of limited extent. Of the newer markers, plasma procollagen-1 N-peptide (PINP) performs best. Treatment with potent bisphosphonates usually produces long-term remission.ConclusionsBoth genetic and environmental factors appear to be important in the aetiology of Paget's disease. Effective long-term disease suppression can be achieved with bisphosphonate treatment.     

Hyperparathyroidism in Paget's disease of bone

The association between Paget's disease and hyperparathyroidism was explored in 12 patients by means of a calcium loading test. Parathyroid adenomata were discovered at surgery in 2 and parathyroid hyperfunction was found in varying degrees in 4 others. Differing responses to the calcium loading test were interpreted as reflecting different stages in the bone formation-resorption disequilibrium found in Pagetic bone. A prolonged imbalance in favour of formation is suggested as constituting a stress on the homeostasis of extracellular fluid calcium levels that leads to parathyroid hyperfunction.     

Genetics of Paget's disease of bone

PDB (Paget's disease of bone) is a common condition characterized by focal increases in bone turnover affecting one or more sites throughout the skeleton. Genetic factors are important in the pathogenesis of PDB and many families have been described where PDB is inherited in an autosomal-dominant fashion. Several candidate loci for susceptibility to PDB and related syndromes have been identified by genome-wide scans and recent evidence suggests that mutations in genes that encode components of the RANK [receptor activator of NF-kappaB (nuclear factor-kappaB)]/NF-kappaB signalling pathway play an important role in the pathogenesis of this group of diseases. Insertion mutations in the TNFRSF11A gene encoding RANK have been identified as the cause of familial expansile osteolysis, some cases of early onset PDB and expansile skeletal hyperphosphatasia. Inactivating mutations in the TNFRSF11B gene that encodes OPG (osteoprotegerin) have been found to cause the syndrome of juvenile PDB. Polymorphisms in OPG also appear to increase the risk of developing PDB. The most important causal gene for classical PDB is Sequestosome 1 (SQSTM1), which is a scaffold protein in the NF-kappaB signalling pathway, and mutations affecting the UBA (ubiquitin-associated) domain of this protein occur in between 20-50% of familial and 10-20% of sporadic PDB cases. The rare syndrome of IBMPFD (inclusion body myopathy, PDB and fronto-temporal dementia) is due to mutations in the VCP gene and these also cluster in the domain of VCP that interacts with ubiquitin, suggesting a common disease mechanism with SQSTM1-mediated PDB.     

Reprint: Paget's disease of bone

ObjectivesTo review recent advance in understanding the causation and management of Paget's disease.Design and methodsWe review recent publications concerning the aetiology of the disease and the use of biochemical markers of bone turnover in diagnosis and treatment.ResultsEpidemiologic studies suggest that Paget's disease is decreasing in prevalence and severity (implying that environmental factors are important) but there is also strong evidence of a genetic predisposition particularly through the SQSTM1 gene.Genome-wide association studies have identified polymorphisms at several other loci that are associated with the disease. Plasma alkaline phosphatase activity (ALP) is widely used, but less helpful in patients with disease of limited extent. Of the newer markers, plasma procollagen-1 N-peptide (PINP) performs best. Treatment with potent bisphosphonates usually produces long-term remission.ConclusionsBoth genetic and environmental factors appear to be important in the aetiology of Paget's disease. Effective long-term disease suppression can be achieved with bisphosphonate treatment.     

Blood pressure in subjects with hypercalcaemia and primary hyperparathyroidism detected in a health screening programme

Primary hyperparathyroidism was the most likely diagnosis in sixty-eight non-thiazide treated patients with hypercalcaemia detected in a health screening. The group included fifty-five females and thirteen males with a mean +/- SEM age of 55.0 +/- 0.7 years. On a pair basis, these patients were compared with a series of sixty-eight age- and sex-matched normocalcaemic subjects selected from the health screening register. Five subjects in each group were receiving medication for hypertension. Systolic and diastolic blood pressures were significantly higher in the hypercalcaemic subjects in the remaining fifty-eight pairs (P less than 0.001). This difference was unrelated to impaired renal filtration and many other factors associated with hypertension. It is concluded that hypercalcaemia and/or other effects of deranged parathyroid function per se may result in a blood pressure elevation on which need not necessarily attain the level of hypertension.     

Diagnosis and treatment of Paget's disease of bone

Paget's disease of bone (PDB) is a metabolic bone disease characterized by increased bone resorption followed by excessive unregulated bone formation. This results in weakened, deformed bones of increased mass in which the collagen fibres assume a haphazard irregular mosaic pattern instead of the normal parallel symmetry. PDB rarely occurs before middle age and its prevalence increases steadily with age. The overall prevalence in Caucasians is approximately 3%; although it appears to be declining. There is a geographic variation in prevalence, with highest rates found in the UK. PDB affects both men and women, with a slight predominance in men. PDB may be asymptomatic or symptomatic, depending on the bones involved; the most common symptom is pain in the affected bone. While its aetiology remains elusive, genetic factors and environmental influences are implicated. In 2002, guidelines for PDB management were developed in Great Britain and have gained worldwide acceptance. In this position paper, an Expert Panel of Canadian endocrinologists and rheumatologists examines current evidence on the diagnosis and treatment of PDB to provide Canadian recommendations. In general, diagnosis may be confirmed both by X-ray and by the biochemical marker serum alkaline phosphatase, which is elevated in 85% of individuals with untreated active PDB. Treatment is indicated for all patients with symptoms and for asymptomatic patients with active PDB in areas of the skeleton with the potential to produce complications of clinical importance. The Panel recommends treating PDB with bisphosphonates that have demonstrated superior efficacy and remission rates.     

Unusual presentation of primary hyperparathyroidism with osteoporosis, hypercalcemia, and normal parathyroid hormone level

We report the case of a woman with osteoporosis, chronic hypercalcemia, and normal levels of parathyroid hormone (PTH). Surgical exploration revealed hyperplasia of the parathyroid glands. Hypercalcemia was corrected immediately by surgery, and this was followed by a dramatic improvement in bone mineral density. This case represents a rarely reported presentation of primary hyperparathyroidism with an atypical laboratory finding.     

Diagnosis and treatment of Paget's disease of bone

Paget's disease of bone (also known as osteitis deformans) is a nonmalignant disease involving accelerated bone resorption followed by deposition of dense, chaotic, and ineffectively mineralized bone matrix. The origin of the disease is unknown, and it is frequently asymptomatic; however, the patient may present with symptoms depending on the bones involved. The most common symptom is pain in the affected bone; neurologic, hearing, vision, cardiac, and oncologic complications are possible. Diagnosis is primarily made by radiographs. Bisphosphonates are the most common treatment.     

Metastatic bone disease and tumour-induced hypercalcaemia: treatment options

Metastatic bone disease in malignancy is responsible for considerable morbidity and mortality. Problems include debilitating bone pain and skeletal-related events (SREs), including tumour-induced hypercalcaemia. This article provides an overview of the different approaches to managing bone disease in malignancy with particular focus on the role of bisphosphonates. The three generations of bisphosphonates are discussed in relation to their role in treating bone pain and hypercalcaemia, and also in terms of their potential for being used in a prophylactic way to prevent or delay SREs.