Low sclerostin levels after long-term remission of acromegaly.

PURPOSE: Bone health is compromised in acromegaly resulting in vertebral fractures (VFs), regardless of biochemical remission. Sclerostin is a negative inhibitor of bone formation and is associated with increased fracture risk in the general population. Therefore, we compared sclerostin concentrations between well-controlled acromegaly patients and healthy controls, and assessed its relationship with bone mineral density (BMD), and VFs in acromegaly. METHODS: Seventy-nine patients (mean age 58.9 ± 11.4 years, 49% women) with controlled acromegaly, and 91 healthy controls (mean age 51.1 ± 16.9 years, 59% women) were included. Plasma sclerostin levels (pg/mL) in patients were measured with an ELISA assay, whereas in controls, serum levels were converted to plasma levels by multiplication with 3.6. In patients, VFs were radiographically assessed, and BMD was assessed using dual X-ray absorptiometry. RESULTS: Median sclerostin concentration in controlled acromegaly patients was significantly lower than in healthy controls (104.5 pg/mL (range 45.7-234.7 pg/mL) vs 140.0 pg/mL (range 44.8-401.6 pg/mL), p < 0.001). Plasma sclerostin levels were not related to age, current growth hormone (GH) or insulin-like factor-1 (IGF-1) levels, gonadal state, treatment modality, remission duration, or BMD, VF presence, severity or progression. CONCLUSION: Patients with long-term controlled acromegaly have lower plasma sclerostin levels than healthy controls, as a reflection of decreased osteocyte activity. Further longitudinal studies are needed to establish the course of sclerostin during different phases of disease and its exact effects in acromegalic osteopathy.

hypercalcaemia due to a calcitriol-producing neuroendocrine tumour.

In this case report, we describe a 40-year-old patient with a large grade 2 pancreatic neuroendocrine tumour (pNET) with spleen metastasis. Albeit radical resection, he developed liver metastasis after 2 years, for which he underwent radio frequency ablation and embolization, and was treated successfully with different subsequent lines of systemic therapy. Eight years after the initial diagnosis, he was admitted for symptomatic and refractory hypercalcaemia, due to calcitriol synthesis by the liver metastasis. After tumour load reduction by hemihepatectomy, there was an initial normalization of hypercalcaemia, until it recurred after 18 months. In this period, the liver metastasis had progressed despite chemo- and immunotherapy. Patient underwent an additional extend hemihepatectomy, from which he recovered well with normalization of calcium levels. This case illustrates the hormonal plasticity of pNETs and shows how prolonged survival can be achieved for metastatic pNET by multimodality approach.

Sclerostin deficiency in humans.

Sclerosteosis and van Buchem disease are two rare bone sclerosing dysplasias caused by genetic defects in the synthesis of sclerostin. In this article we review the demographic, clinical, biochemical, radiological, and histological characteristics of patients with sclerosteosis and van Buchem disease that led to a better understanding of the role of sclerostin in bone metabolism in humans and we discuss the relevance of these findings for the development of new therapeutics for the treatment of patients with osteoporosis.

Van Buchem disease: clinical, biochemical, and densitometric features of patients and disease carriers.

Van Buchem disease (VBD) is a rare bone sclerosing dysplasia caused by the lack of a regulatory element of the SOST gene, which encodes for sclerostin, an osteocyte-derived negative regulator of bone formation. We studied the demographic, clinical, biochemical, and densitometric features of 15 patients with VBD (12 adults and 3 children) and 28 related carriers of the gene mutation. The most common clinical findings in patients were facial palsy (100%) and various degrees of hearing impairment (93%); raised intracranial pressure had been documented in 20%. The clinical course of the disease appeared to stabilize in adulthood, with the majority of patients reporting no progression of symptoms or development of complications with time. Carriers of the disease had none of the clinical features or complications of the disease. Sclerostin could be detected in the serum in all but 1 VBD patients (mean 8.0 pg/mL; 95% confidence interval [CI], 4.9-11.0 pg/mL), and were lower than those of carriers (mean 28.7 pg/mL; 95% CI, 24.5-32.9 pg/mL; p < 0.001) and healthy controls (mean 40.0 pg/mL; 95% CI, 34.5-41.0 pg/mL; p < 0.). Serum procollagen type 1 amino-terminal propeptide (P1NP) levels were also significantly higher in adult patients (mean 96.0; 95% CI, 54.6-137.4 ng/mL versus mean 47.8; 95% CI, 39.4-56.2 ng/mL, p = 0.003 in carriers and mean 37.8; 95% CI, 34.5-41.0 ng/mL, p = 0.028 in healthy controls) and declined with age. Bone mineral density (BMD) was markedly increased in all patients (mean Z-score 8.7 ± 2.1 and 9.5 ± 1.9 at the femoral neck and spine, respectively); BMD of carriers was significantly lower than that of patients but varied widely (mean Z-scores 0.9 ± 1.0 and 1.3 ± 1.5 at the femoral neck and spine, respectively). Serum sclerostin levels were inversely correlated with serum P1NP levels (r = -0.39, p = 0.018) and BMD values (femoral neck r = -0.69, p < 0.001; lumbar spine r = -0.78, p < 0.001). Our results show that there is a gene-dose effect of the VBD deletion on circulating sclerostin and provide further in vivo evidence of the role of sclerostin in bone formation in humans. The small amounts of sclerostin produced by patients with VBD may explain their milder phenotype compared to that of patients with sclerosteosis, in whom serum sclerostin is undetectable.

Increased circulating levels of FGF23: an adaptive response in primary hyperparathyroidism?

INTRODUCTION: Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are major players in the bone-parathyroid-kidney axis controlling phosphate homeostasis. In patients with primary hyperparathyroidism (PHPT), data on the relationship between PTH and FGF23 are scarce and not always concordant. OBJECTIVE: The aim of our study was to evaluate the relationship between PTH and FGF23 in patients with PHPT and in euparathyroid patients cured after successful parathyroidectomy (PTx). PATIENTS AND METHODS: Twenty-one patients with PHPT and 24 patients in long-term cure after successful PTx (EuPTH) were studied. All patients underwent biochemical evaluation of renal function, parathyroid status, vitamin D status, bone turnover markers, and serum intact FGF23 levels. RESULTS: Mean serum FGF23 concentration was significantly higher in PHPT than in EuPTH patients (50.8±6.1 vs 33.1±2.6 pg/ml, P=0.01). FGF23 levels significantly correlated with PTH levels (r=0.361, P=0.02), also after correction for 1,25(OH)(2)D levels (r=0.419, P=0.01). FGF23 levels showed a significant negative correlation with 1,25(OH)(2)D, which was more pronounced in PHPT than in EuPTH patients (r=-0.674, P=0.001, vs r=-0.509, P=0.01). CONCLUSION: Our findings suggest that in PHPT, FGF23 levels are increased independent of 1,25(OH)(2)D levels. The more pronounced negative relationship between FGF23 and 1,25(OH)(2)D in the presence of high circulating PTH levels suggests that the increase in FGF23 levels may be an adaptive mechanism to counteract the PTH-induced increase in 1,25(OH)(2)D levels, although not completely overriding it.

Serum sclerostin levels in Paget's disease and prostate cancer with bone metastases with a wide range of bone turnover.

Evidence has been accumulating for the role of osteocytes as key players in the regulation of bone remodeling. One of the main products of these cells, sclerostin, inhibits bone formation and may also stimulate bone resorption. Circulating sclerostin has been evaluated in humans, but data are scarce in patients with different rates of bone turnover. To address this issue we evaluated serum sclerostin levels in patients with Paget's disease of bone (PD) and in patients with prostate cancer metastatic to the skeleton (PC). Sclerostin levels were measured in 88 patients with PD, 20 patients with PC and 237 healthy individuals (113 men and 124 women, aged 20 to 77 years). Bone turnover was evaluated by measuring serum levels of procollagen type 1 amino-terminal propeptide (P1NP) in all individuals studied and ß-carboxy-terminal cross-linking telopeptide of type I collagen (ß-CTX) only in patients. Patients were aged between 45 and 88 years and had a wide range of bone turnover: serum P1NP 9.2 to 1872 ng/ml and ß-CTX 50 to 3120 pg/ml. Patients with PD and with PC had significantly higher mean serum sclerostin levels (53.1 ± 22.7 pg/ml and 56.6 ± 25.8 pg/ml, respectively) compared to healthy controls (38.1 ± 12.1 pg/ml) (p<0.001). Serum sclerostin levels were significantly correlated with P1NP in all (n=345) studied subjects (r=0.32, p<0.001). Circulating sclerostin levels are significantly increased in patients with increased bone turnover, regardless of underlying pathology. These increased levels may be due to a compensatory response to the increased number of osteoblasts at affected skeletal sites and may contribute to the increased bone resorption in patients with PC .

Patients with sclerosteosis and disease carriers: human models of the effect of sclerostin on bone turnover.

Sclerosteosis is a rare bone sclerosing dysplasia, caused by loss-of-function mutations in the SOST gene, encoding sclerostin, a negative regulator of bone formation. The purpose of this study was to determine how the lack of sclerostin affects bone turnover in patients with sclerosteosis and to assess whether sclerostin synthesis is decreased in carriers of the SOST mutation and, if so, to what extent this would affect their phenotype and bone formation. We measured sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and cross-linked C-telopeptide (CTX) in serum of 19 patients with sclerosteosis, 26 heterozygous carriers of the C69T SOST mutation, and 77 healthy controls. Chips of compact bone discarded during routine surgery were also examined from 6 patients and 4 controls. Sclerostin was undetectable in serum of patients but was measurable in all carriers (mean 15.5 pg/mL; 95% confidence interval [CI] 13.7 to 17.2 pg/mL), in whom it was significantly lower than in healthy controls (mean 40.0 pg/mL; 95% CI 36.9 to 42.7 pg/mL; p < 0.001). P1NP levels were highest in patients (mean 153.7 ng/mL; 95% CI 100.5 to 206.9 ng/mL; p = 0.01 versus carriers, p = 0.002 versus controls), but carriers also had significantly higher P1NP levels (mean 58.3 ng/mL; 95% CI 47.0 to 69.6 ng/mL) than controls (mean 37.8 ng/mL; 95% CI 34.9 to 42.0 ng/mL; p = 0.006). In patients and carriers, P1NP levels declined with age, reaching a plateau after the age of 20 years. Serum sclerostin and P1NP were negatively correlated in carriers and age- and gender-matched controls (r = 0.40, p = 0.008). Mean CTX levels were well within the normal range and did not differ between patients and disease carriers after adjusting for age (p = 0.22). Our results provide in vivo evidence of increased bone formation caused by the absence or decreased synthesis of sclerostin in humans. They also suggest that inhibition of sclerostin can be titrated because the decreased sclerostin levels in disease carriers did not lead to any of the symptoms or complications of the disease but had a positive effect on bone mass. Further studies are needed to clarify the role of sclerostin on bone resorption.

Glucocorticoids are not always deleterious for bone.

A 23-year-old man with the rare sclerosing bone disorder van Buchem disease presented with progressively worsening headaches that eventually became persistent and associated with papilledema. Increased intracranial pressure was diagnosed, and the patient had a ventriculoperitoneal drain inserted as well as simultaneously receiving treatment with prednisone. Before starting treatment, there was biochemical evidence for increased bone turnover and for steady increases in bone mineral density (BMD) at the spine and total hip despite the patient having reached his peak height of 197 cm at the age of 19 years. Treatment with prednisone for 2 years resulted in biochemical and histologic suppression of bone formation as well as of bone resorption and arrest of further bone accumulation. Our data suggest that glucocorticoids (GCs) may represent an attractive alternative to the high-risk surgical approaches used in the management of patients with progressive sclerosing bone disorders. Our findings also suggest that whereas sclerostin may not be required for the action of GCs on bone formation, it may well be important for the action of GCs on bone resorption. The exact mechanism by which sclerostin may be involved in the regulation of bone resorption is as yet to be explored.