Bone metabolism in patients with primary hyperparathyroidism before and after surgery

Primary hyperparathyroidism (PHPT) is accompanied with a reduced bone mineral density (BMD) and an increased risk of fracture. Surgery is the only option for cure. It is hypothesized that in patients with PHPT bone metabolism normalizes after parathyroidectomy (PTX) and that BMD gradually increases. Fifty-two patients with PHPT who underwent surgery were prospectively followed for 1 year. Biochemical analyses were performed at baseline and 1, 4, 7 days; 6 weeks; and 3, 6, and 12 months, and BMD before and one year after surgery. Parathyroid hormone (PTH), calcium, and the bone resorption marker dropped immediately, but transiently after PTX, bone formation decreased more slowly. Osteoprotegerin (OPG) as well as cathepsin K did not show significant changes. BMD of the lumbar spine, but not of the femoral neck, increased significantly within one year after surgery. Moderate correlations existed between the changes of total calcium, ionized calcium, as well as bone-specific alkaline phosphatase and changes of the lumbar BMD. Patients who needed postoperative supplementation with calcium and vitamin D had significantly higher PTH levels. Some gender-specific differences in patients with PHPT were observed. In patients with PHPT, males appear to be more severely affected than females. Within the first year after PTX, bone metabolism normalized, and BMD of the lumbar spine increased. Patients who needed a supplementation with calcium and vitamin D after PTX preoperatively had higher serum levels of PTH.     

Cohort study on effects of parathyroid surgery on multiple outcomes in primary hyperparathyroidism

Objectives To assess the effects of surgery compared with conservative treatment (no surgery) for primary hyperparathyroidism.Design Cohort study.Setting Nationwide Danish cohort.Participants 3213 patients, mean age 61 (SD 16) years, with a diagnosis of primary hyperparathyroidism between 1980 and 1999. 1934 (60%) underwent surgery and 1279 (40%) were treated conservatively.Main outcome measures Occurrence of fractures, osteoporosis, kidney or urinary tract stones, acute myocardial infarction, angina pectoris, cardiac arrhythmias, arterial hypertension, heart failure, stroke, acute pancreatitis, stomach or duodenal ulcers, muscle pain, malignant diseases, psychiatric disorders, and mortality.Results At diagnosis of primary hyperparathyroidism, patients who subsequently underwent surgery had a lower prevalence of previous fracture (odds ratio 0.64, 95% confidence interval 0.51 to 0.80), acute myocardial infarction (0.59, 0.42 to 0.83), stroke (0.57, 0.37 to 0.88), psychiatric disorders (0.54, 0.31 to 0.94), and painful muscle disorders (0.44, 0.26 to 0.76), whereas kidney stones (2.49, 1.93 to 3.23) and acute pancreatitis (2.77, 1.33 to 5.76) were more prevalent. After diagnosis, the risks of fractures (hazards ratio 0.69, 0.56 to 0.84) and gastric ulcers (0.59, 0.41 to 0.84) were lower in patients treated surgically than those treated conservatively. Events involving kidney or urinary tact stones were more prevalent in patients treated surgically than patients treated conservatively (1.87, 1.30 to 2.68). Mortality was lower in patients treated surgically (0.65, 0.57 to 0.73).Conclusions Patients treated surgically for primary hyperparathyroidism have a lower prevalence of fractures and gastric ulcers than patients treated conservatively. The type of treatment had no effect on the occurrence of cardiovascular events.     

Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study

AimTo study the risk of renal stone episodes and risk factors for renal stones in primary hyperparathyroidism before and after surgery.DesignRegister based, controlled retrospective follow up study.SettingTertiary hospitals in Denmark.Participants674 consecutive patients with surgically verified primary hyperparathyroidism. Each patient was compared with three age- and sex-matched controls randomly drawn from the background population. Hospital admissions for renal stone disease were compared between patients and controls. Risk factors for renal stones among patients were assessed.ResultsRelative risk of a stone episode was 40 (95% confidence interval 31 to 53) before surgery and 16 (12 to 23) after surgery. Risk was increased 10 years before surgery, and became normal more than 10 years after surgery. Stone-free survival 20 years after surgery was 90.4% in patients and 98.7% in controls (risk difference 8.3%, 4.8% to 11.7%). Patients with preoperative stones had 27 times the risk of postoperative stone incidents than controls. Before surgery, males had more stone episodes than females and younger patients had more stone episodes than older patients. Neither parathyroid pathology, weight of removed tissue, plasma calcium levels, nor skeletal pathology (fractures) influenced the risk of renal stones. After surgery, younger age, preoperative stones and ureteral strictures were significant risk factors for stones.ConclusionsThe risk of renal stones is increased in primary hyperparathyroidism and decreases after surgery. The risk profile is normal 10 years after surgery. Preoperative stone events increase the risk of postoperative stones. Stone formers and non-stone formers had the same risk of skeletal complications.

What is already known on this topic

Patients with primary hyperparathyroidism have an increased risk of renal stone eventsThe extent to which parathyroid surgery reduces the risk of further stones is unclear

What this study adds

The risk of a new stone event was 8.3% higher in patients than in controls after surgeryIn patients with stone disease before operation the risk rate for a postoperative stone event was 27times that in controlsThe risk of a renal stone event was higher than the risk among controls until more than 10 years after surgery     

Basal and stimulated calcitonin secretion in primary hyperparathyroidism before and after parathyroidectomy

To investigate calcitonin secretion in primary hyperparathyroidism, basal and stimulated (3 mg Ca++/kg body weight/10 min) immunoreactive calcitonin plasma levels were studied before parathyroidectomy. Plasma calcitonin levels were raised in 50% of patients regardless of sex, but a significant correlation between basal plasma calcium and calcitonin was found only in males. A reduced calcitonin response to calcium infusion was observed in all patients. Parathyroidectomy invariably induced a normalization of calcitonin basal levels. Our findings confirm the existence of a decreased parafollicular cell reserve probably as a consequence of the persistent hypercalcemic state in hyperparathyroid patients and suggest that it is more frequent in females.     

Bone fracture in elderly female with primary hyperparathyroidism: relationship among renal function, vitamin D status and fracture risk

Among 12 aged postmenopausal females with primary hyperparathyroidism, 5 had no bone fracture and 7 had fractures. Both serum 1,25 (OH)2D levels and creatinine clearance values in patients with fracture were significantly lower than those without fracture (p less than 0.025). In addition, significant positive correlation was observed between serum 1,25 (OH)2D levels and creatinine clearance values (p less than 0.05). These data suggest that decreased serum 1,25 (OH)2D level due to renal dysfunction may causally correlate to bone fracture in postmenopausal primary hyperparathyroidism.     

Effect of alpha-difluoromethylornithine in lung metastases before and after surgery of primary adenocarcinoma tumors in mice

The depletion of polyamines by alpha-difluoromethylornithine (DFMO) treatment of mice after subcutaneous inoculation of adenocarcinoma M3 cells caused a remarkable inhibition in the growth rate of primary tumors as well as in the occurrence and number of lung metastases with a concomitant increase in survival time. Tumor-bearing mice submitted to the surgical removal of primary tumors and then treated with alpha-difluoromethylornithine also showed a significant reduction of lung metastases. In addition, a lower number of lung metastatic nodules correlated with decreased levels of polyamines in the same tissue. The described approach provides a useful experimental model for studies in human cancer therapy.     

Pathophysiology of primary hyperparathyroidism

Parathyroid gland is the overall regulatory organ within the systemic calcium homeostasis. Through cell surface bound calcium-sensing receptors external calcium inversely regulates release of parathyroid hormone (PTH). This mechanism, which is voltage independent and most sensitive around physiologic calcium concentrations, is regulated through a 120 kDa calcium sensing receptor, CaR. Inherited inactivation of this receptor is the cause for familial hypocalciuric hypercalcemia (FHH). Parallel research identified the 550 kDa glycoprotein megalin, which also is expressed on the parathyroid cell surface, as another potential calcium sensing protein. Although this protein expresses numerous calcium binding sites on its external domain, its main function may be calcium sensitive binding and uptake of steroid hormones, such as 25-OH-vitamin D3 (bound to vitamin D binding protein) and retinol. In hyperparathyroidism (HPT), excessive PTH is secreted and the calcium sensitivity of the cells reduced, i.e. the set-point, defined as the external calcium concentration at which half-maximal inhibition of PTH release occurs, shifted to the right. Pathological cells have reduced expression of both CaR and megalin, and reduced amount of intracellular lipids, possibly including stored steroid hormones. A number of possible genetic disturbances have been identified, indicating multifactorial reasons for the disease. In postmenopausal women, however, the individual group with highest incidence of disease, a causal relation to reduced effect of vitamin D is possible. An incipient renal insufficiency with age, lack of sunshine in the Northern Hemisphere, and an association to the baT haplotype of the vitamin D receptor supports this theory. This review summarizes data on regulation of PTH release, dysregulation in HPT, as well as proliferation of parathyroid cells.     

Value of 1-alpha-hydroxy vitamin D3 in treatment of primary hyperparathyroidism before parathyroidectomy.

The postoperative course of six patients with primary hyperparathyroidism and obvious radiological evidence of bone disease pretreated with 1-alpha-hydroxy vitamin D3 (1 alpha HCC) was indistinguishable from that of six patients with a similar clinical and radiological picture who were not pretreated. 1alphaHCC may increase the hypercalcaemia in some cases and cannot be recommended for the routine preparation of such patients for surgery.     

Possibilities and limits of the medical treatment for primary hyperparathyroidism

Clinically obvious primary hyperparathyroidism is only curable by surgery. Medical treatment is debatable under other circumstances: mild chronic hypercalcemia, patients who refuse surgery, serious coexisting medical problems and recurrence or persistence of PHPT after surgical treatment. Prior to medical treatment, the usual common management of any mild hypercalcemia must be taken. The potential medical treatments are: (1) the inhibition of parathyroid hormone (PTH) secretion, and (2) the inhibition of the effects of PTH. The substances of these two main types are successively described. Nevertheless, no ideal medical treatment of PHPT is actually available.     

Effect of NHS walk-in centre on local primary healthcare services: before and after observational study

ObjectiveTo assess the effect of an NHS walk-in centre on local primary and emergency healthcare services.DesignBefore and after observational study.SettingLoughborough, which had an NHS walk-in centre, and Market Harborough, the control town.Participants12 general practices.ResultsThe change between the before and after study periods was not significantly different in the two towns for daily rate of emergency general practice consultations (mean difference −0.02/1000 population, 95% confidence interval −0.75 to 0.71), the time to the sixth bookable routine appointment (−0.24 half-days, −1.85 to 1.37), and daily rate of attendances at out of hours services (0.07/1000 population, −0.06 to 0.19). However, attendance at the local minor injuries unit was significantly higher in Loughborough than Market Harborough (rate ratio 1.22, 1.12 to 1.33). Non-ambulance attendances at accident and emergency departments fell less in Loughborough than Market Harborough (rate ratio 1.17, 1.03 to 1.33).ConclusionsThe NHS walk-in centre did not greatly affect the workload of local general practitioners. However, the workload of the local minor injuries unit increased significantly, probably because it was in the same building as the walk-in centre.

What is already known on this topic

Walk-in centres are well established in North America but differ from NHS centres as they are run by doctors not nurses

What this study adds

Introduction of an NHS walk-in centre did not affect the workload of local general practitionersAttendance increased at the minor injuries unit, which was in the same buildingNon-ambulance attendances at accident and emergency departments decreased but not by as much as in the control area