Stephen J. Gallacher

Cancer-Associated Hypercalcemia: Morbidity and Mortality: Clinical Experience in 126 Treated Patients

STUDY OBJECTIVE To review the effects of antihypercalcemic treatment on morbidity and mortality in cancer-associated hypercalcemia. DESIGN Retrospective study of 126 consecutive patients with cancer-associated hypercalcemia. SETTING Inpatient referrals from a teaching hospital in the United Kingdom. INTERVENTION Medical antihypercalcemic therapy supplemented by specific anticancer therapy where possible. MEASUREMENTS AND MAIN RESULTS Median survival was 30 days. Survival did not differ in patients treated with different antihypercalcemic regimens but was longer (median, 135 days; P less than 0.001) in a subgroup of 26 patients for whom specific anticancer therapy was available. Polyuria and polydipsia improved after therapy in 83% of cases, central nervous system symptoms in 71%, constipation in 70%, nausea and vomiting in 56%, anorexia in 50%, and malaise and fatigue in 47% (all significant, P less than 0.001, pre-treatment compared with post-treatment). Pain control improved in only 23% of cases (not significant). Only 7% of patients with post-treatment serum calcium values above 3.50 mmol/L improved clinically compared with 80% whose calcium values fell below 2.80 mmol/L (P less than 0.001). Corresponding figures for the proportion of patients discharged from the hospital were 0% and 68% (P less than 0.001). CONCLUSIONS Life expectancy is poor in cancer-associated hypercalcemia even in patients who are actively treated. Antihypercalcemic therapy has an important palliative role, however, because symptoms are usually improved and, in many cases, patients may be made well enough to be discharged from the hospital during the terminal stages of their illness.

The prevalence of familial hypocalciuric hypercalcemia.

Familial hypocalciuric hypercalcemia is said to be an extremely rare condition but is clinically important because it can be confused with primary hyperparathyroidism. The biochemical features of the two conditions are similar, but the former is benign while the latter can have serious clinical consequences with patients occasionally proceeding to parathyroidectomy. It is therefore important to differentiate accurately between the two. With this in mind it would be useful to know the prevalence of familial hypocalciuric hypercalcemia when considering the differential diagnosis of primary hyperparathyroidism. However, as far as we are aware, no estimate of the prevalence of this condition can be found in the literature. We describe how an estimate was made of the prevalence of familial hypocalciuric hypercalcemia in the west of Scotland. We estimate the prevalence to be 1 in 78,000 at least.

Metabolic, inflammatory and haemostatic effects of a low‐dose continuous combined HRT in women with type 2 diabetes: potentially safer with respect to vascular risk?

background  Conventional hormone replacement therapy (HRT) containing conjugated equine oestrogen (CEE) and medroxyprogesterone acetate (MPA) increases triglyceride, C‐reactive protein (CRP) and coagulation Factor VII concentrations, potentially explaining their increased coronary heart disease (CHD) and stroke risk.

Refracture following fracture liaison service assessment illustrates the requirement for integrated falls and fracture services.

The Fracture Liaison Service (FLS) allows appropriate antiosteoporosis therapy to be targeted to potentially reduce future fracture risk. A proportion of these treated patients will still experience a further fracture. This work reviews the characteristics of these patients. Data were collated for patients >65 years old presenting to the South Glasgow FLS between January 2001 and August 2004. There were 2,489 patients who presented (incident fracture group), and 129 (5.2%) sustained an additional fracture (refracture group). Median age of the incident fracture group was 77.8 years vs. 80.6 years for the refracture group (P = nonsignificant). The refracture group was determined according to whether their incident fracture was hip (n = 47) or nonhip (n = 82). When the incident fracture was hip, a refracture was more likely to be a further hip fracture (χ2 = 14.4, P = 0.002) and patients refractured sooner (median time to refracture 194 [range 10–1,134] days vs. 258 [range 6–1,081] days [nonhip]) (P = nonsignificant). In the refracture group, 76% of patients were already on osteoporosis treatment after their incident fracture. Patients over 65 years of age presenting to FLS who sustain an additional fracture are older; are likely to sustain another hip fracture after an incident hip fracture; often refracture early, particularly when the incident fracture is of the hip; and are often already on antiosteoporosis treatment. Therefore, it is important to identify these high-risk patients and offer a combined approach of prompt drug treatment through a systematic and specialist osteoporosis management team along with reducing any reversible falls risk factors.

Direct and indirect assessment of the parathyroid hormone response to pamidronate therapy in Paget's disease of bone and hypercalcaemia of malignancy

In patients with either Pagets disease or hypercalcaemia associated with malignancy (HCM) we have assessed the parathyroid response to pamidronate therapy, both by immunoassay of serum intact parathyroid hormone PTH (1-84) and by measurement of indirect parameters of PTH bioactivity, tubular maximum reabsorption of phosphate (TmPO4/GFR) and nephrogenous cyclic AMP (NcAMP). In 12 patients with Pagets disease, therapy with pamidronate produced a small but significant decrease in adjusted serum calcium within the reference interval which was accompanied by a progressive increase in PTH (1-84) secretion and a corresponding fall in TmPO4/GFR and increase in NcAMP. In 12 patients with HCM pretreatment, PTH (1-84) concentrations were suppressed, whilst mean TmPO4/GFR was reduced and NcAMP was increased, compatible in most patients, with parathyroid hormone-related peptide (PTHrP) driven hypercalcaemia. Therapy with pamidronate produced the expected fall in serum calcium but caused an increase in PTH (1-84) secretion in the presence of absolute hypercalcaemia. The initial subnormal TmPO4/GFR decreased further to a nadir on day 5, and there was a corresponding further increase in NcAMP. By day 7, however, when PTH (1-84) concentrations were maximal, there was a significant paradoxical rise in TmPO4/GFR and a corresponding decrease in NcAMP. These data are consistent with a variable trigger point for PTH (1-84) secretion, one consequence of which is a reduction in the risk of hypocalcaemia following pamidronate. The results have major clinical implications for the interpretation of PTH (1-84) measurements in patients who are being treated or about to be treated for bone disease or for hypercalcaemia of malignancy (HCM).(ABSTRACT TRUNCATED AT 250 WORDS)

THE LOSS OF CIRCADIAN RHYTHM FOR INTACT PARATHYROID HORMONE AND NEPHROGENOUS CYCLIC AMP IN PATIENTS WITH PRIMARY HYPERPARATHYROIDISM

The measurement of serum intact parathyroid hormone (PTH) (1‐84) over a 24‐h period has shown the existence of a circadian rhythm in normal males which is absent in patients with primary hyperparathyroidism. The physiological significance of this observation is reflected in the presence of parallel changes in nephrogenous cyclic adenosine monophosphate (N‐cAMP) in normals which are also absent in primary hyperparathyroidism. Serum calcium, adjusted for variations in albumin concentrations, showed a transient fall in normal subjects prior to the nocturnal rise in PTH (1‐84). A similar transient fall in serum adjusted calcium was observed in the hyperparathyroid patients. Serum phosphate showed a circadian rhythm in normal subjects, and an attenuated rhythm persisted in primary hyperparathyroidism. These data suggest that both ionic factors and higher centres play important roles in the fine control of PTH (1‐84) secretion.

A comparison of low versus high dose pamidronate in cancer-associated hypercalcaemia

Pamidronate has been demonstrated to be an effective agent in the treatment of cancer-associated hypercalcaemia. The dose regime, however, remains controversial. In this study 16 patients with cancer-associated hypercalcaemia were given 30 mg pamidronate by intravenous infusion and 16 were given 90 mg also by infusion. Groups were well-matched in terms of tumour types, bone metastases, pre-treatment serum calcium and creatinine, fasting urinary calcium/creatinine ratio, nephrogenous cAMP and the renal tubular threshold for phosphate reabsorption (TmPO4). The calcium lowering effect was similar in both treatment groups with nadir at day 6 of mean (+/- SEM) 2.48 mmol/l (+/- 0.06) in the 30 mg group and at day 9 in the 90 mg group of 2.51 mmol/l (+/- 0.03) (P less than 0.01). 10 patients in the 30 mg group and 8 in the 90 mg group were normocalcaemic at this point. Similarly when those patients with more severe hypercalcaemia (greater than 3.30 mmol/l, n = 7 in each group) were analysed separately, no significant difference was evident between the two groups. Urinary calcium/creatinine ratios fell to a nadir at day 6 in both groups of 0.33 (+/- 0.05) (30 mg group) and 0.37 (+/- 0.10) (90 mg group) (P less than 0.01). Follow-up results after the initial 9 days showed the mean time to relapse to be 38 days (range 18-90) in the 30 mg group and 34 days (11-105) in the 90 mg group.(ABSTRACT TRUNCATED AT 250 WORDS)

Medical training and the hospital at night: an oxymoron?

Context  Attempts to reduce doctors’ working hours and streamline postgraduate medical training may mean junior doctors’ out‐of‐hours experience is reduced. It is also proposed that, in the UK, compulsory clinical (Foundation Programme) competencies are to be accomplished in 1 year rather than 2 years as they are at present. This observational study was performed to examine the scope of opportunity available to junior doctors to achieve such competencies while working on a ‘Hospital at Night’ (H@N) team.

Formulary management of drugs for cancer-associated hypercalcaemia.

SummaryHypercalcaemia associated with cancer is seen not infrequently in hospital practice and can be a source of considerable morbidity. Over the past decade, our understanding of the pathogenesis of this syndrome has advanced, allowing improved treatment protocols. Because one of the principal abnormalities relates to an increase in bone resorption, antiresorptive agents such as calcitonin and the bisphosphonates have been shown to be of value. In the medium to longer term, the bisphosphonates {particularly pamidronic acid [pamidronate; aminohydroxypropylidene bisphosphonate (APD)] and clodronic acid [clodronate; dichloromethyl bisphosphonate (Cl2MDP)]} appear to be more efficacious in terms of their calcium-lowering effect than calcitonin, and also appear to be associated with fewer adverse effects than most other agents.However, the importance of energetic re-expansion of the extracellular space with 0.9% sodium chloride before bisphosphonate therapy is extremely important. Cancer-associated hypercalcaemia, especially with squamous cancer, is often associated with the production of parathyroid hormone-related protein (PTHrP). Where this is the case, it usually reflects the presence of more advanced disease with shortened life expectancy, and poorer response to calcium-lowering therapy. Multiple treatments with larger doses of bisphosphonate may be required for these patients.

Women over 75 with fragility fractures should have DEXA

The recent NICE guidance on osteoporosis has generated much controversy and the publication of “alternative” guidelines.1 An aspect which has escaped attention is the advice that bone density scanning by dual energy x ray absorptiometry (DEXA) may not be required in women aged ≥75 who have had a fragility fracture. This has been incorporated into the osteoporosis direct enhanced service agreement …