Michael A. Davies

Association Between Vertebral Fracture and Increased Mortality in Osteoporotic Patients

Determinants of mortality were studied in a prospective study of 677 women and men with primary or secondary osteoporosis. Prevalent vertebral fractures were associated with increased mortality, but other known predictors of mortality explain a significant proportion of the excess risk.

The role of 1,25‐dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency

OBJECTIVE We wished to assess the effect of changes In the plasma concentration of 1,25‐dihydroxyvitamin D on the plasma elimination half‐time for 25‐hydroxyvitamin D In man.

Bone Loss in Celiac Disease Is Related to Secondary Hyperparathyroidism

Celiac disease is a major cause of intestinal malabsorption. Previous studies have demonstrated that celiac disease is associated with significant osteoporotic bone loss. These studies have suggested that successful treatment of the malabsorption is associated with amelioration of the bone loss. Such studies have failed to examine bone mass at peripheral skeletal sites which is more likely to be responsive to changes in parathyroid hormone (PTH) in response to calcium malabsorption. We have examined bone density in the lumbar spine, femoral neck, and distal forearm in 35 patients with celiac disease who had been established on gluten‐free diet. In addition, the concentrations of PTH and 1,25‐dihydroxyvitamin D (1,25(OH)2D) were measured. Bone density was below that expected for the subjects age and gender at all sites. This was most marked in the distal forearm where the bone density was 1.40 SD below expected (p < 0.0001). In the forearm, there was a negative relationship between bone density and PTH concentration (r = −0.49, p = 0.009). In the forearm and lumbar spine, there was a negative relationship between 1,25(OH)2D concentration and bone density. Bone mass was not related to the concentration of 25‐hydroxyvitamin D at any of the skeletal sites measured. Bone density is reduced in the peripheral skeleton in celiac disease and this deficit persists despite treatment with apparent normalization at axial skeletal sites. This reduction in bone mass is related to the presence of secondary hyperparathyroidism which should be sought in all patients with treated celiac disease.

Detection of canine distemper virus in 100% of Paget's disease samples by in situ-reverse transcriptase-polymerase chain reaction.

Previous evidence implicating paramyxoviruses in the aetiopathology of Pagets disease of bone has been controversial. While several groups have demonstrated the presence of paramyxoviruses using electron microscopy, immunohistochemistry, and molecular biological techniques, others have found no evidence of viruses using reverse transcriptase-polymerase chain reaction (RT-PCR). We have previously provided evidence that canine distemper virus (CDV) is present in approximately 65% of samples of pagetic bone, using in situ hybridization and RT-PCR; however, these results have been criticized. To further investigate the possible Role of CDV, we have now developed the technique of in situ-RT-PCR (IS-RT-PCR) to examine for the presence of CDV-nucleocapsid (CDV-N) ribonucleic acid (RNA) in pagetic bone. Control samples consisted of uninvolved sites from patients with the disease, normal bone, and several active remodeling states. IS-RT-PCR was optimized to detect CDV-N using distemper-infected vero cells. The specificity of the technique was confirmed using vero cells infected with CDV, which showed amplified signal following IS-RT-PCR, and cells infected with measles virus (MV), in which no positive signal for CDV was detected by IS-RT-PCR. Following conventional in situ hybridization, CDV-N was detectable in 10 of 15 pagetic bone samples. However, after five, and particularly 10, cycles of IS-RT-PCR, CDV-N was found in all 15 samples. There was no evidence of CDV in four samples from uninvolved sites from pagetic patients, or in any of the other control samples. In this study, using the novel technique of IS-RT-PCR, CDV was found to be present in 100% of pagetic samples examined. There was no evidence of the virus in any of the control samples, including samples of bone from uninvolved sites from patients with Pagets disease. These results provide additional proof that CDV is present within pagetic bone and further support the hypothesis that paramyxoviruses are involved in the etiopathology of Pagets disease.

Clodronate Reduces Vertebral Fracture Risk in Women With Postmenopausal or Secondary Osteoporosis: Results of a Double-Blind, Placebo-Controlled 3-Year Study

The efficacy of oral clodronate 800 mg daily to reduce vertebral fractures was studied in 593 women with postmenopausal or secondary osteoporosis. The incidence of vertebral fractures was significantly reduced by 46%. The effect was not modified by the underlying cause of osteoporosis or other baseline factors including bone mineral density, QUS, weight, and smoking.

Impaired glucose tolerance and insulin insensitivity in primary hyperparathyroidism

OBJECTIVE A high prevalence of diabetes mellitus has been shown in patients with primary hyperparathyroidism (PHPT). However, it is unclear whether this is related to the metabolic abnormalities in PHPT or to the presence of other risk factors for glucose intolerance in these patients. The aim of our study was to determine whether glucose intolerance and insulin insensitivity occur in subjects with PHPT who do not have other risk factors for diabetes mellitus.

Do men and women fracture bones at similar bone densities

Abstract: When the World Health Organization (WHO) guidelines for the definition of osteoporosis in postmenopausal women were identified similar proposals were not developed for men as there was insufficient evidence about the relationship between bone density and fracture in men. We have therefore examined the relationship between bone density and vertebral fracture in men and women attending for assessment of possible osteoporosis. Two hundred and sixty-four women (age 64 [SD 10] years) and 37 men (age 55 [10] years) were studied. Bone density was measured in the lumbar spine and femoral neck by dual-energy X-ray absorptiometry and expressed both as bone mineral density (BMD; g/cm2) and as T-scores. In both sexes there was a sigmoid relationship between the cumulative frequency of vertebral fracture and bone density at both sites. There was a linear relationship between the log odds of fracture and bone mass for both sexes and both sites (r= 0.97–0.99; p<0.0001). The slope of these lines was significantly steeper for men than women. The BMD at which there was 50% risk of fracture was higher in men than women (0.908 vs 0.844 g/cm2). The difference between the slopes was similar when the bone mass was expressed as a T-score. However, the T-score associated with 50% prevalence of fracture was similar in the two sexes (F: −2.77 vs M: −2.60). We conclude that although there is a different relationship between bone density and fracture in the two sexes the current WHO definition of osteoporosis in postmenopausal women can be appropriately applied to men.

Vitamin D intoxication causes hypercalcaemia by increased bone resorption which responds to pamidronate.

OBJECTIVE Vitamin D intoxication is a relatively rare but treatable cause of hypercalcaemia. In the past this has been undertaken using corticosteroids. Previous observations have suggested that there is increased bone resorption in hypervitaminosis D. If this were to be the case, specific inhibitors of bone resorption might provide more effective treatment. We have therefore studied the mechanisms of hypercalcaemia and response to therapy in a group of patients with vitamin D intoxication.

Calcium-sensing receptor mutations in familial hypocalciuric hypercalcaemia with recurrent pancreatitis

OBJECTIVE Pancreatitis is an unusual complication of the benign disorder familial hypocalciuric hypercalcaemia (FHH) such that it could represent a distinct subgroup of FHH. In order to study this, we investigated three FHH kindreds with recurrent pancreatitis for mutations of the extracellular calcium‐sensing receptor (CaR) to identify a possible common genetic aetiology for typical FHH and that associated with pancreatitis.

Vitamin D Nutrition and Bone Disease in Adults

The consequences of vitamin D deficiency upon the skeleton are well known and management in the absence of renal failure is relatively straightforward. Vitamin D, either by mouth or parenterally will correct the deficiency and heal the osteomalacia. The mechanisms underlying the causation of vitamin D deficiency are now better understood and indicate the importance of underlying calcium malabsorption and secondary hyperparathyroidism leading to 1,25(OH)2D-induced catabolism of 25(OH)D and possibly also of vitamin D itself. In such situations, e.g., gastrointestinal and pancreaticobiliary disease, calcium supplementation in addition to vitamin D is indicated. The reasons behind nutritional vitamin D deficiency and the possible role of meat in protecting from osteomalacia await further elucidation, but from epidemiological studies, calcium deficiency, per se, is not implicated in the etiopathogenesis. The concept of vitamin D insufficiency is poorly understood, and difficult to define since a single value or close range of serum 25(OH)D values is unlikely to predict the needs of all subjects. Oral calcium intake and renal function are also likely to be relevant to the level of 25(OH)D which is found to be sufficient or insufficient for any given individual to maintain a normal serum calcium level without secondary hyperparathyroidism. There is increasing evidence that vitamin D insufficiency, by leading to sustained hyperparathyroidism, is prejudicial to the skeleton, particularly cortical bone. Since it is without symptoms until fractures occur, it should be actively sought in those clinical situations now recognized as contributing to risk. It can only be identified by the periodic measurement of serum 25(OH)D and the calcitropic hormones PTH and 1,25(OH)2D. In addition, BMD should be measured in a predominantly cortical site such as the proximal forearm, as well as the more conventional sites of spine and hip. The implications of these recommendations are an increase in the use of assays for PTH and vitamin D metabolites in the groups of subjects discussed in this review. Patients with chronic malabsorption states might reasonably be expected to have measurements performed twice-yearly. When vitamin D insufficiency is found, treatment with either vitamin D, calcium or both will be necessary, depending on the etiology of the insufficiency state in the inividual. In some malabsorptive states, calcium malabsorption is the cause of hyperparathyroidism and oral calcium alone can be used to reverse excess PTH activity in those with an adequate state of vitamin D nutrition. However, even in those vitamin D replete individuals, vitamin D catabolism will be enhanced and a small additional oral dose of vitamin D can do no harm. Regular monitoring of PTH and vitamin D metabolites will remain a necessity to ensure continued efficacy of treatment. Current recommendations for dietary supplements of vitamin D are clearly inadequate [61]. There is compelling evidence for supplements of 800 IU per day in the elderly and other high risk populations. Such a dose is safe and without side effects. The available evidence suggests that this should be combined with calcium supplements of 1200 mg/day [19] and that the current UK recommendations for a daily calcium intake of 700 mg contrast with those from the USA at 1,200 mg for people over 50 years old. Physicians need to be aware of both the small but important problem of vitamin D depletion and osteomalacia with its sometimes ambiguous presentation, and the more common but covert vitamin D (and calcium) insufficiency with its widespread and varied clinical associations.