Drug-Related Hypercalcemia.

This review focuses on the commonly prescribed medicaments that can be responsible for hypercalcemia, considering the prevalence, the predominant pathophysiological mechanisms, and the optimal medical management of each drug-induced hypercalcemia. Vitamin D supplements and 1α-hydroxylated vitamin D analogues increase intestinal calcium absorption, renal calcium reabsorption as well as bone resorption. In patients with hypoparathyroidism receiving recombinant human PTH, transient hypercalcemia can occur because of overtreatment, usually during acute illness. Thiazide-induced hypercalcemia is mainly explained by enhanced renal proximal calcium reabsorption, changing preexistent asymptomatic normocalcemic or intermittently hypercalcemic hyperparathyroidism into the classic hypercalcemic hyperparathyroidism. Lithium causes hypercalcemia mainly by drug-induced hyperparathyroidism.

X-linked hypophosphatemia and burosumab: Practical clinical points from the French experience.

Hereditary hypophosphatemia with increased FGF23 levels are rare inherited metabolic diseases characterized by low serum phosphate because of impaired renal tubular phosphate reabsorption. The most common form is X-linked hypophosphatemia (XLH), secondary to a mutation in the PHEX gene. In children, XLH is often manifested by rickets, delayed development of gait, lower limb deformities, growth retardation, craniosynostosis, and spontaneous dental abscesses. In adults, patients present diffuse musculoskeletal pain (bone and joints), early osteoarthritis, entesopathies, pseudo-fractures, muscular weakness, and severe dental damage. Conventional medical management is based on the combined administration of oral phosphate supplementation with active vitamin D analogs. Treatment with the recently approved anti-FGF23 burosumab is an alternative, especially in severe forms. Burosumab restores phosphate reabsorption in the proximal tubule and stimulates the endogenous synthesis of calcitriol. In Europe, burosumab has been approved for the treatment of XLH with radiographic evidence of bone disease in pediatric patients from one year of age and in adults. This manuscript will discuss the specific management of burosumab in children and adolescents in daily practice.

Management of X-linked hypophosphatemia in adults.

X-linked hypophosphatemia (XLH) is caused by mutations in the PHEX gene which result in Fibroblast Growth Factor-23 (FG-F23) excess and phosphate wasting. Clinically, XLH children present with rickets, bone deformities and short stature. In adulthood, patients may still be symptomatic with bone and joint pain, osteomalacia-related fractures or pseudofractures, precocious osteoarthrosis, enthesopathy, muscle weakness and severe dental anomalies. Besides these musculoskeletal and dental manifestations, adult XLH patients are also prone to secondary and tertiary hyperparathyroidism, cardiovascular and metabolic disorders. Pathophysiology of hyperparathyroidism is only partially understood but FGF23 excess and deficient production of calcitriol likely contributes to its development. Similarly, the pathophysiological mechanisms of potential cardiovascular and metabolic involvements are not clear, but FGF-23 excess may play an essential role. Treatment should be considered in symptomatic patients, patients undergoing orthopedic or dental surgery and women during pregnancy and lactation. Treatment with oral phosphate salts and active vitamin D analogs has incomplete efficacy and potential risks. Burosumab, a recombinant human monoclonal antibody against FGF-23, has proven its efficacy in phase 2 and phase 3 clinical trials in adult patients with XLH, but currently its position as first line or second line treatment differ among the countries.

Impaired quality of life in adults with X-linked hypophosphatemia and skeletal symptoms.

OBJECTIVE: Adults with X-linked hypophosphatemia (XLH) may suffer from skeletal symptoms leading to functional disability. No data on their quality of life (QoL) have been reported so far. Our objectives were to evaluate the QoL and its determinants in XLH adults. PATIENTS AND METHODS: We conducted a prospective study in XLH adults, who consulted for musculoskeletal symptoms between 2013 and 2014. We assessed their QoL using HAQ, RAPID3 and SF36, and analysed the variables associated with low QoL. We compared their QoL to that of patients affected with axial spondyloarthritis (ax-SpA) (paired on age and gender), a rheumatologic disorder with a known low QoL. RESULTS: Fifty-two XLH adults (37 women (71.1%); mean age 41.8±13.3 years) were included; 44 (84.6%) patients had an altered QoL. Increased age and presence of structural lesions were significantly associated with worse QoL (HAQ, RAPID3) (P<0.05). Presence of enthesopathies was significantly associated with worse RAPID3 (OR=4.45 (1.09-18.29), P=0.038). Treatment with phosphate supplements and vitamin D in XLH adults were significantly associated with a better SF36-mental component score (OR=0.14 (0.03-0.57), P=0.007 and OR=0.26 (0.07-0.98), P=0.047 respectively). QoL was significantly worse in XLH than in ax-SpA adults (VAS pain, SF36-PCS, RAPID3) (P<0.05). CONCLUSION: Our study showed i) QoL of XLH adults is altered and significantly worse than that of ax-SpA patients (VAS pain, SF36-PCS and RAPID3), ii) structural lesions and especially enthesopathies are associated with a worse QoL and iii) treatment using phosphate supplements and/or vitamin D is associated with a better mental health score.

Therapeutic management of hypophosphatemic rickets from infancy to adulthood.

In children, hypophosphatemic rickets (HR) is revealed by delayed walking, waddling gait, leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses, and growth failure. If undiagnosed during childhood, patients with hypophosphatemia present with bone and/or joint pain, fractures, mineralization defects such as osteomalacia, entesopathy, severe dental anomalies, hearing loss, and fatigue. Healing rickets is the initial endpoint of treatment in children. Therapy aims at counteracting consequences of FGF23 excess, i.e. oral phosphorus supplementation with multiple daily intakes to compensate for renal phosphate wasting and active vitamin D analogs (alfacalcidol or calcitriol) to counter the 1,25-diOH-vitamin D deficiency. Corrective surgeries for residual leg bowing at the end of growth are occasionally performed. In absence of consensus regarding indications of the treatment in adults, it is generally accepted that medical treatment should be reinitiated (or maintained) in symptomatic patients to reduce pain, which may be due to bone microfractures and/or osteomalacia. In addition to the conventional treatment, optimal care of symptomatic patients requires pharmacological and non-pharmacological management of pain and joint stiffness, through appropriated rehabilitation. Much attention should be given to the dental and periodontal manifestations of HR. Besides vitamin D analogs and phosphate supplements that improve tooth mineralization, rigorous oral hygiene, active endodontic treatment of root abscesses and preventive protection of teeth surfaces are recommended. Current outcomes of this therapy are still not optimal, and therapies targeting the pathophysiology of the disease, i.e. FGF23 excess, are desirable. In this review, medical, dental, surgical, and contributions of various expertises to the treatment of HR are described, with an effort to highlight the importance of coordinated care.

Primary hyperparathyroidism in pregnancy.

Primary hyperparathyroidism (PHPT) is rarely diagnosed during pregnancy but is associated with significant maternal and fetal morbidity and mortality. Information on appropriate management is limited. We reviewed the medical literature through December 2012 for key articles on PHPT during pregnancy, focusing on large series. Clinical knowledge in this area is restricted to isolated case reports and a few retrospective studies. Diagnosis can be difficult, owing to the non-specific nature of signs and symptoms of hypercalcemia during pregnancy. Pregnant women with a calcium level over 2.85 mmol/L (11.4 mg/dL) and prior pregnancy loss are at a particularly high risk of maternal complications (hypercalcemic crisis, nephrolithiasis, pancreatitis, etc.) and fetal loss. Around one-half of neonates born to mothers with untreated PHPT have hypocalcemia and tetany. Algorithms proposed for the management of the pregnant woman with PHPT are not evidence based, reflecting the paucity of data. Treatment should thus be individually tailored. Gestational age and the severity of hypercalcemia should be taken into account when assessing the risk-benefit balance of a conservative approach (hyperhydration and vitamin D supplementation) versus parathyroid surgery. Current evidence supports parathyroidectomy as the main treatment, performed preferably during the second trimester, when the serum calcium is above 2.75 mmol/L (11 mg/dL). In the patients with mild forms of PHPT, which are nowadays the most frequent, a conservative management is generally preferred.

Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing's syndrome.

CONTEXT: Mitotane is highly effective in the long-term management of Cushing's syndrome but has a slow onset of action. Mitotane combined with fast-acting steroidogenesis inhibitors might avoid the need for emergency bilateral adrenalectomy in patients with severe hypercortisolism. OBJECTIVE: Our objective was to assess the efficacy and safety of combination therapy with mitotane, metyrapone, and ketoconazole in severe ACTH-dependent Cushing's syndrome. PATIENTS, DESIGN, AND SETTING: Eleven patients with severe Cushing's syndrome participated in this follow-up study in a tertiary referral hospital. INTERVENTIONS: High-dose therapy combining mitotane (3.0-5.0 g/24 h), metyrapone (3.0-4.5 g/24 h), and ketoconazole (400-1200 mg/24 h) was initiated concomitantly. Twenty-four-hour urinary free cortisol (UFC) excretion (normal values 10-65 µg/24 h) was monitored. RESULTS: Data are reported as medians (range). All 11 patients experienced a marked clinical improvement. UFC excretion fell rapidly from 2737 µg/24 h (range 853-22,605) at baseline to 50 µg/24 h (range 18-298) (P = 0.001) within 24-48 h of treatment initiation and remained low to normal on the combination therapy. In seven patients, metyrapone and ketoconazole were discontinued after 3.5 months (range 3.0-6.0) of combination therapy, and UFC excretion remained controlled by mitotane monotherapy (UFC 17 µg/24 h, range 5-85; P = 0.016). Five patients became able to undergo etiological surgery and are presently in remission. Four of them recovered normal adrenal function after mitotane discontinuation. Adverse effects were tolerable, consisting mainly of gastrointestinal discomfort and a significant rise in total cholesterol and γ-glutamyl transferase levels (P = 0.012 and P = 0.002, respectively). CONCLUSIONS: When surgical treatment for severe ACTH-dependent Cushing's syndrome is not feasible, combination therapy with mitotane, metyrapone, and ketoconazole is an effective alternative to bilateral adrenalectomy, a procedure associated with significant morbidity and permanent hypoadrenalism.

McCune-Albright syndrome and acromegaly: effects of hypothalamopituitary radiotherapy and/or pegvisomant in somatostatin analog-resistant patients.

BACKGROUND: Acromegaly, which may be present in patients with McCune-Albright syndrome (MCAS), in association with café-au-lait spots, precocious puberty, and fibrous dysplasia, is often difficult to treat surgically because skull base bone dysplasia prevents the removal of the pituitary adenoma. Somatostatin analogs (SAs) generally give only partial responses. The use of radiotherapy (RT) is controversial because of a possible risk of bone sarcomatous transformation. AIM: This study was a retrospective analysis of the efficacy and adverse effects of different treatment modalities in six patients with both MCAS and acromegaly. PATIENTS AND METHODS: Because surgery was impossible and SA failed to normalize GH/IGF-I hypersecretion, five of the six patients received fractionated RT (45-55 Grays). Three patients (two with previous RT) were also prescribed pegvisomant. We analyzed the clinical features of acromegaly, GH, and IGF-I concentrations and bone radiological features. RESULTS: GH and IGF-I concentrations fell after RT (median follow-up, 5 yr; range, 0.5-9 yr). Symptoms of acromegaly improved in parallel. Bone sarcomatous transformation was only noted in one patient in a region (the mandible) outside the radiation field. RT alone and/or combined with SA failed to normalize GH/IGF-I levels in the five patients concerned. In contrast, IGF-I levels normalized very rapidly (5-9 months) in the three patients receiving pegvisomant (10-20 mg/d). CONCLUSION: RT may be an option for the treatment of acromegaly in patients with MCAS when surgery is impossible and SA therapy is ineffective. However, although no bone sarcomatous transformation was observed within the radiation field in this series, this risk cannot be ruled out. As shown in this small series of severely affected patients, pegvisomant therapy may thus be useful to normalize IGF-I levels rapidly.