Tenofovir-induced osteopenia and hyperparathyroidism: A case report and literature review.

Tenofovir disoproxil fumarate is the first-line antiviral therapy for chronic viral hepatitis B, but long-term use is associated with renal failure and hypophosphatemic osteomalacia. Tenofovir disoproxil fumarate-induced osteoporosis and secondary hyperparathyroidism are less commonly reported. Herein, we describe the case of a patient with bone and multijoint pain who was initially misdiagnosed as having normocalcemic primary hyperparathyroidism associated with prolonged exposure to tenofovir disoproxil fumarate. The patient's 24-h urinary calcium and phosphorus excretion levels and serum calcium levels were at the lower end of the normal range. After reviewing these findings, the diagnosis was amended to osteoporosis and secondary hyperparathyroidism caused by tenofovir disoproxil fumarate. In this report, we describe the differences in clinical and laboratory manifestations of hyperparathyroidism induced by tenofovir disoproxil fumarate and normocalcemic primary hyperparathyroidism. We also discuss relevant pathophysiological mechanisms and propose a feasible treatment strategy.

Successful Reversal of Furosemide-Induced Secondary Hyperparathyroidism With Cinacalcet.

Secondary hyperparathyroidism (SHPT) is a rare complication of furosemide therapy that can occur in patients treated with the loop diuretic for a long period of time. We report a 6-month-old 28-weeks premature infant treated chronically with furosemide for his bronchopulmonary dysplasia, who developed hypocalcemia and severe SHPT, adversely affecting his bones. Discontinuation of the loop diuretic and the addition of supplemental calcium and calcitriol only partially reversed the SHPT, bringing serum parathyroid hormone level down from 553 to 238 pg/mL. After introduction of the calcimimetic Cinacalcet, we observed a sustained normalization of parathyroid hormone concentration at 27 to 63 pg/mL and, with that correction, of all biochemical abnormalities and healing of the bone disease. No adverse effects were noted. We conclude that in cases of SHPT due to furosemide in which traditional treatment fails, there may be room to consider the addition of a calcimimetic agent.

[Citrate anticoagulation in acute renal replacement therapy : Method of choice]. / Zitratantikoagulation in der akuten Nierenersatztherapie : Methode der Wahl.

BACKGROUND: Anticoagulation is prerequisite for efficient continuous renal replacement therapy (CRRT). Premature clotting of the extracorporeal system leads to therapy interruptions, is costly, and causes relevant blood losses. REGIONAL ANTICOAGULATION: Regional citrate anticoagulation (RCA) achieves reliable coagulation inhibition and is clearly superior to heparin with regard to filter survival time. Due to its mode of action, a bleeding risk can be excluded. RCA with the commercial machine solutions is safe and has been promoted as the new standard anticoagulant for CRRT. Bioincompatibility reactions like leukocyte degranulation and complement system activation are ameliorated under RCA. DISCUSSION: An assumed survival advantage of RCA could not be confirmed. In case of severe liver insufficiency and lactic acidosis, RCA can lead to metabolic complications. Despite calcium supplementation, the calcium net balance of RCA is often negative. Long treatment durations can therefore cause secondary hyperparathyroidism and in extreme cases osteomalacia. RCA is also a valuable option in intermittent hemodialysis.

Osteomalacia in a patient with Paget's bone disease treated with long-term etidronate.

A 93 year-old woman with Paget's disease of bone had been treated with etidronate without interruption during 20 years. The daily dose was usual (5mg/kg/day) but this prescription had never been stopped by her physicians. Two fractures had already occurred in pagetic (right tibia) and non pagetic bones (right fibula) within the last 2 years, and she presented rib fractures, another right tibia fracture and right femur fracture during hospitalization time. X-rays films showed major osteolysis of left ulna and right tibia. Blood samples and technetium bone scan brought no evidence for sarcoma or lytic evolution of the disease. A transiliac bone biopsy on non pagetic bone site confirmed the diagnosis of osteomalacia (increased osteoid parameters), with secondary hyperparathyroidism (hook resorption). In Paget's disease of bone, continuous treatment by etidronate may induce generalized osteomalacia, and increase the risk of fracture in both pagetic and non-pagetic bones. Whereas physicians and pharmaceutical industry try to improve the observance of those drugs, this striking observation also points out that a prescription always needs to be updated.

Prognostic role of serum parathyroid hormone levels in advanced prostate cancer patients undergoing zoledronic acid administration.

BACKGROUND: Secondary hyperparathyroidism is frequent in prostate cancer patients with bone metastases, and this condition is worsened by the administration of potent bisphosphonates. Serum parathyroid hormone (PTH) elevation can impair the efficacy of these drugs in terms of survival. METHODS: The prognostic role of elevated serum PTH levels at baseline and after 3 months of zoledronic acid administration was assessed prospectively in 643 bone metastatic prostate cancer patients enrolled in a prospective randomized, placebo-controlled study. RESULTS: On multivariate analysis, after adjusting for major prognostic factors and bone turnover markers, elevated baseline serum PTH level was negatively associated with overall survival (hazard ratio [HR], 1.448; 95% confidence interval [CI], 1.045-2.006; p < .03) in zoledronic acid-treated patients but not in placebo-treated patients. In patients with normal baseline PTH levels, there was a trend but insignificant association between zoledronic acid administration and a better survival outcome than with placebo (HR, 0.81; 95% CI, 0.65-1.01; p = .065), whereas a trend in the opposite direction was observed in patients with elevated PTH levels (HR, 1.45; 95% CI, 0.87-2.39; p = .151); interaction test, p = .040. Elevated serum PTH level after 3 months of zoledronic acid treatment was not significantly associated with survival outcome. CONCLUSIONS: Secondary hyperparathyroidism has a negative prognostic impact in metastatic prostate cancer patients undergoing zoledronic acid administration. Counteracting elevated PTH levels by adequate doses of vitamin D may improve the efficacy of this drug.

Secondary hyperparathyroidism but stable bone-mineral density in patients with chronic myeloid leukemia treated with imatinib.

Imatinib is currently the standard treatment for chronic myeloid leukemia(CML). Previous studies have shown that imatinib affects bone metabolism in CML patients. However, these effects are not well-studied prospectively. The authors studied bone-mineral density (BMD) and bone metabolism in 17 CML patients and matched controls in 2007 and now repeated the analyses prospectively in 2011. All CML patients were in complete cytogenetic remission during this 4-year period and treated with 400 mg imatinib q.d. (n 5 15) or 600 mg imatinib q.d. (n 5 2). Mean treatment duration was 102 months (range 69­129) in 2011. The authors found that serum levels of parathyroid hormone increased significantly in the patients between 2007 and 2011, and seven out of 17 patients had secondary hyperparathyroidism in 2011. However, the mean areal and volumetric BMDs were stable in the CML patients over the 4-year-observation period. Moreover, the CML patients had significantly higher volumetric BMD in the cortical compartment when compared with controls in 2011 and 2007. Thus, despite a high incidence of secondary hyperparathyroidism,there were no signs of osteoporosis or osteomalacia in imatinib-treated CML patients as suggested earlier.

Insufficient bilateral femoral subtrochanteric fractures in a patient receiving imatinib mesylate.

We present a case of insufficient bilateral femoral subtrochanteric fractures in a patient who was treated with imatinib mesylate, an anticancer drug, for 1 year after a diagnosis of chronic myelogenous leukemia (CML). A 60-year-old woman presented with bilateral thigh pain for 6 months. A plain radiograph revealed bilateral progressive insufficient fractures on the subtrochanteric areas of the femurs. MRI of the femurs revealed incomplete stress fractures and no evidence of bone metastasis on either femur. Bone densitometry showed normal T-scores around the hip joint and spine. The patient had normal serum levels of calcium, vitamin D derivatives, and thyroid hormones. Serum phosphate levels were decreased, and parathyroid hormone levels were increased. Serum osteocalcin and urinary N-telopeptide of collagen cross-links (NTx) were both decreased. A bone biopsy demonstrated normocellular marrow without leukemic cells. A histomorphometric evaluation of her bones revealed reduced bone turnover despite secondary hyperparathyroidism. The serum markers for bone metabolism and histomorphometric evaluations in this patient suggest that the drug may have an effect on bone metabolism. These effects could be seen for both bone formation and resorption: this could result in impaired bone mineralization, a severely suppressed bone turnover rate, insufficient fractures, and bone necrosis, which are sometimes seen with long-term use of bisphosphonates. To our knowledge, this is the first case of an insufficient bilateral femoral shaft fracture that is potentially related to the use of imatinib mesylate in a patient with CML. Careful examination of bone metabolism should be performed in patients with CML because imatinib mesylate treatment is a lifelong process.

[Role of bone gammagraphy in the diagnosis of secondary osteomalacia in a patient treated with tenofovir]. / Utilidad de la gammagrafía ósea en el diagnóstico de osteomalacia secundaria en un paciente en tratamiento con tenofovir.

It is reported a HIV infected patient under antiretroviral therapy including tenofovir therapy who was referred to the Nuclear Medicine Department to complete bone pain study. A bone scan was performed at 3 hours after the injection of 740 MBq of 99mTc-MDP, revealing an abnormal distribution with characteristic changes compatible with osteomalacia. In further analysis, a secondary hyperparathyroidism and osteomalacia were diagnosed in the context of Fanconi syndrome, an infrequent complication described in patients under treatment with tenofovir.

Vitamin D levels and bone turnover in epilepsy patients taking carbamazepine or oxcarbazepine.

PURPOSE: Evidence suggests that enzyme-inducing antiepileptic drugs (AEDs) may decrease serum 25-hydroxyvitamin D (25-OHD) levels and increase bone turnover. We sought to determine whether these are affected by treatment with carbamazepine (CBZ) or oxcarbazepine (OXC). METHODS: We measured serum levels of 25-OHD, parathyroid hormone (PTH), osteocalcin (OCLN), bone alkaline phosphatase (BAP), and urinary N-telopeptides of type I collagen cross-links (NTX) in normal controls (n=24) and in epilepsy patients taking CBZ (n=21) or OXC (n=24) in monotherapy. CBZ patients were subsequently switched overnight to OXC monotherapy, and after 6 weeks, the tests were repeated. RESULTS: 25-OHD levels were lower in each drug-treated group (OXC, 19.4+/-2.3 pg/ml; CBZ, 20.4+/-2.4) than in the controls (27.5+/-2.8) (ANOVA, p=0.052). This difference was significant for the OXC group (p<0.05). PTH, BAP, and NTX did not differ significantly among groups. OCLN levels were somewhat elevated in the OXC group (2.79+/-0.47 ng/ml) and more clearly and significantly elevated in the CBZ group (3.63+/-0.36) compared with controls (2.38+/- 0.41) (p=0.053). Because the data were very similar between OXC and CBZ groups, they were combined to increase statistical power. The combined drug-treatment group had significantly higher BAP (p=0.02) and lower 25-OHD (p=0.015) than did controls. The latter remained significant even after accounting for the confounding effects of age on 25-OHD levels (p<0.05). No significant differences were found after CBZ patients were switched to OXC. CONCLUSIONS: Epilepsy patients taking OXC or CBZ have significantly lower 25-OHD than do normal controls, with a pattern of changes in other bone biomarkers suggestive of secondary hyperparathyroidism. It may be prudent for patients taking CBZ or OXC to be prescribed 25-OHD replacement.

[Treatment of adynamic bone disease with the complete replacement from calcium carbonate to sevelamer hydrochloride].

The aim of this study was to examine the therapeutic effect of hypocalcemic stimulation caused by sevelamer hydrochloride (SH) administration on adynamic bone disease (ABD). The subjects were 28 maintenance hemodialysis (HD) patients who had remained in ABD state in spite of no administration of vitamin D(3) since HD induction (15 males and 13 females;12 diabetic patients and 16 non-diabetic patients). The mean age was 61.8+/-9.5 years and the mean HD duration was 5.5+/-3.9 years. The calcium concentration in the dialysate was 3.0 mEq/L. We made the final daily dose of SH after two months the same as the first daily dose of calcium carbonate (CC) in the following manner. At first we administered only CC at breakfast and lunch and SH at supper. And for the next two weeks we administered CC at breakfast and SH at lunch and supper. And for the final two weeks we administered only SH. After that we increased the dose of SH as much as possible. We evaluated the therapeutic effect of the above treatment on ABD using intact-osteocalcin (iOC) [Teijin. Tokyo] as a marker before and 6, 12 months after the beginning of the replacement. If iOC Ievel of 30 to 70 ng/mL showed normal tumover bone (NTB), 5 cases (17.9%) changed into NTB in 6 months. 9 cases (32.1%) changed into NTB in 12 months and one case (3.6%) changed into ostitis fibrosa in 12 months. It is thought that SH is effective for the treatment of ABD but we have to be careful for ostitis fibrosa.

[Lithium, a potentially dangerous drug]. / Lithium, een potentieel gevaarlijk geneesmiddel.

Two patients with a bipolar disorder, a woman aged 56 and a woman aged 68, who had used lithium for more than 30 years, were seen with side effects from this medication. Both patients were treated by their general practitioner and had not visited a psychiatrist for many years. The first patient had a chronic lithium intoxication with cerebellar signs and eventually coma, diabetes insipidus, hyperthyroidism, hyperparathyroidism and psoriasis. After 6 weeks of treatment in the intensive-care unit she made a good recovery. The second patient had several lithium side effects. She was diagnosed with diabetes insipidus, hyperparathyroidism due to a parathyroid adenoma, hypothyroidism and a sick-sinus syndrome. A pacemaker was implanted 4 years earlier. The adenoma was surgically removed. After other medication was tried, the patient was once again given lithium, on which she was able to function well. The first patient had lithium concentrations above the therapeutic value for several years and both patients experienced a delay before their signs and symptoms were attributed to lithium. Lithium treatment should be monitored by an experienced psychiatrist.

Pathophysiology of bone loss in patients receiving anticonvulsant therapy.

Many studies have shown that patients taking antiepileptic drugs (AEDs) are at increased risk for metabolic bone disease and low bone mineral density. Although early reports of bone disease in patients with epilepsy often involved institutionalized patients, who may be at risk because of lack of physical activity, reduced sunlight exposure, and poor nutrition, low bone density has also been reported in well-nourished, ambulatory outpatients with epilepsy. Traditionally, attention to the problem of AED-induced bone loss has been focused on those drugs that induce the hepatic cytochrome P450 enzyme system, thereby increasing the metabolism of vitamin D. However, the mechanisms of AED-induced bone loss appear to be multiple, and all types of AEDs are potentially implicated. Besides hepatic enzyme induction, mechanisms may include direct effects of AEDs on bone cells, resistance to parathyroid hormone, inhibition of calcitonin secretion, and impaired calcium absorption. An understanding of bone biology and the pathophysiology of bone loss can aid in the identification and monitoring of patients at risk and in the planning of appropriate prophylactic and therapeutic measures, by which most of the morbidity associated with AED-induced bone loss can be prevented.

[Fluoride toxicity]. / Tossicità del fluoro.

Many years have passed since domestic water fluoridation was adopted to reduce the incidence of caries in developed countries; however, since there is an additional dose of fluorides ingested with foods and drinks prepared with such waters, the problem has emerged of possible adverse effects on health associated to them, so that in some countries fluorine integrator selling is allowed only with preventive medical prescription. Owing to the affinity for calcifited tissues, fluorine has a powerful effect on bone cellular order (mediated by growth factors' upregulation system IGF-2, TGF-beta, PDGF, bFGF, EGF, BMP-2 and PTH), on function and length, since it can provoke chronic joints-pain, ligaments-calcification, osteosclerosis. Moreover, sodium-fluoride may cause adverse effects on testicular activity (connected to oxidative-stress depending on increased activity of peroxidases and catalases) due to inhibition of 2 androgenesis-regulator enzymes DELTA(5)b-HSD and 17beta-HSD. Furthermore, insoluble gut formed calcium-fluoride may be responsible for hypocalcemia inducing a secondary hyperparathyroidism with bone matrix resorption, osteoporosis, osteomalacia and, perhaps, lowered level of phosphorus. At encephalic level, then, high doses of fluorine cause the onset of neurological symptoms and of a decreased spontaneous motor activity due to a reduction in the number of nicotinic acetylcholine receptors. Nevertheless, epidemiological studies about fluoride toxicity have established that such oligoelement may be safely used at odontoiatric dosages.

[Hyperparathyroidism secondary to anticonvulsant treatment]. / Hyperparatyreoidisme sekundaert til antiepileptisk behandling.

Treatment with some anticonvulsants is known to lead to liver enzyme induction. Two cases suggest that this interaction is also the mechanism behind anticonvulsant osteomalacia, which is characterised by hypocalcaemia, elevated alkaline phosphatase, and low 25(OH) cholecalciferol.

[Lithium treatment and hyperparathyroidism]. / Litiumbehandling og hyperparatyreoidisme.

BACKGROUND: Lithium treatment, which is extensively used in bipolar affective disorders, may give rise to hypercalcaemia and sometimes to irreversible hyperparathyroidism. MATERIAL AND METHODS: We present a patient who developed hyperparathyroidism following long-term treatment with lithium. RESULTS: After 15 years on lithium the patient was diagnosed with hypercalcaemia; at the same time the patient stopped her lithium medication. Two years later she developed depression with psychotic symptoms and was given electroconvulsive treatment. Measurements of serum calcium and parathormon showed that she had developed hyperparathyroidism. Neck exploration was performed, and two parathyroid adenomas (weight 650 mg and 880 mg), which had been detected by scintigraphy, were removed. Lithium treatment was restarted. One year later she was normocalcaemic and her mood was normal. INTERPRETATION: In lithium-induced hyperparamyroidism, lithium should be replaced with other mood stabilizers, preferably an antiepilepticum. If cessation of lithium therapy does not lead to normocalcaemia, parathyroidectomy is indicated.

Secondary hyperparathyroidism exacerbation: a rare side-effect of interferon-alpha?

Recombinant human interferon alpha (alpha IFN) is the only treatment with proven benefit for chronic hepatitis C virus (HCV) infection. Nevertheless its use in some susceptible individuals has led to the development or aggravation of different autoimmune conditions. We report the case of a 20 year old woman on peritoneal dialysis with chronic lobular hepatitis secondary to HCV infection who developed de novo psoriasis 9 months after starting treatment with alpha-IFN. In addition to psoriasis, alpha-IFN prescription was also concurrent with an unexpected and refractory secondary hyperparathyroidism exacerbation initially characterized by a marked reduction of serum calcium levels and a consequential increase of PTH. Both complications disappeared after drug withdrawal. The clinical sequence makes an alpha-IFN-induced autoimmune side effect the most plausible hypothesis. The case is discussed and some possible etiopathogenic factors are briefly reviewed.