Giant parathyroid lipoadenoma case report: A parathyroid phenomenon.

INTRODUCTION: Parathyroid lipoadenomas are a rare parathyroid phenomenon and an unusual cause of primary hyperparathyroidism. A difficult diagnosis to make, there are less than 100 cases in the literature since they were first described in 1958, and to our knowledge this is the largest parathyroid lipoadenoma to be reported. PRESENTATION OF CASE: A minimally-invasive parathyroidectomy with intraoperative parathyroid hormone monitoring was performed in the case of a male with a large neck mass and symptomatic primary hyperparathyroidism. A giant parathyroid lipoadenoma was excised, with an appropriate decrease in intraoperative parathyroid hormone level observed. DISCUSSION: This lesion poses a challenge to the surgeon, radiologist and pathologist alike and is an important addition to the scant literature available. Clinically it presents similarly to a simple adenoma. The high adipose content of this lesion leads to difficulty localising it on imaging, and the histology study can lead pathologists astray. CONCLUSION: We highlight the importance of having the parathyroid lipoadenoma as a differential diagnosis for patients who develop primary hyperparathyroidism.

Primary Hyperparathyroidism during Pregnancy: Two Tales with Different Outcomes.

Primary hyperparathyroidism (PHPT) is rare in pregnancy. This condition is challenging to diagnose and manage due to the limited diagnostic and therapeutic options that are safe during pregnancy. If not diagnosed and managed in a timely manner, serious maternal and foetal complications may occur. We report two cases, one with surgical intervention and one without, to show the importance of timely surgical intervention and discuss the challenges in the management of PHPT in pregnancy.

Delayed and significant hypercalcaemia due to teriparatide therapy: a case report and review.

INTRODUCTION: Transient hypercalcaemia due to teriparatide occurs in up to 11% of patients though delayed hypercalcaemia (> 24 h post injection) is rare. We report the case of a female who developed significant delayed hypercalcaemia after teriparatide treatment for osteoporosis and review other cases in the literature to date. CASE REPORT: A 72-year-old female on teriparatide for the treatment of osteoporosis was found to have hypercalcaemia (3.30 mmol/l) on routine testing approximately 3 months after starting therapy. Serum calcium pretreatment was normal at 2.39 mmol/l. She was admitted to the hospital for investigations which identified a serum 25-hydroxyvitamin D of 94 nmol/l, a low parathyroid hormone of 6.0 pg/ml, and normal test results for 1,25 dihydroxyvitamin D (115 pmol/l), parathyroid hormone-related peptide (< 1.4 pmol/ml), serum electrophoresis and angiotensin-converting enzyme (39 IU/l). CT abdomen, pelvis, and thorax revealed no evidence of malignancy and an isotope bone scan ruled out skeletal metastases. Serum calcium normalised (2.34 mmol/l) several days after stopping teriparatide and calcium supplements and administering intravenous fluid. On restarting teriparatide, delayed hypercalcaemia reoccurred and treatment was switched to denosumab. DISCUSSION: Delayed moderate to severe hypercalcaemia (serum calcium > 3.0 mmol/l) due to teriparatide is rare but may lead to therapy withdrawal. The underlying predisposing risk factors remain unclear and highlight the importance of a routine serum calcium assessment on therapy.

Characteristics, management and outcomes of primary hyperparathyroidism from 2009 to 2021: a single centre report from South Africa.

BACKGROUND: There has been a notable shift towards the diagnosis of less severe and asymptomatic primary hyperparathyroidism (PHPT) in developed countries. However, there is a paucity of recent data from sub-Saharan Africa (SSA), and also, no reported data from SSA on the utility of intra-operative parathyroid hormone (IO-PTH) monitoring. In an earlier study from Inkosi Albert Luthuli Central Hospital (IALCH), Durban, South Africa (2003-2009), majority of patients (92.9%) had symptomatic disease. The aim of this study was to evaluate the clinical profile and management outcomes of patients presenting with PHPT at IALCH. METHODS: A retrospective chart review of patients with PHPT attending the Endocrinology clinic at IALCH between July 2009 and December 2021. Clinical presentation, laboratory results, radiologic findings, surgical notes and histology were recorded. RESULTS: Analysis included 110 patients (87% female) with PHPT. Median age at presentation was 57 (44; 67.5) years. Symptomatic disease was present in 62.7% (n:69); 20.9% (n:23) had a history of nephrolithiasis and 7.3% (n:8) presented with previous fragility fractures. Mean serum calcium was 2.87 ± 0.34 mmol/l; median serum-PTH was 23.3 (15.59; 45.38) pmol/l, alkaline phosphatase 117.5 (89; 145.5) U/l and 25-hydroxyvitamin-D 42.9 (33.26; 62.92) nmol/l. Sestamibi scan (n:106 patients) identified an adenoma in 83.02%. Parathyroidectomy was performed on 84 patients with a cure rate of 95.2%. Reasons for conservative management (n:26) included: no current surgical indication (n:7), refusal (n:5) or deferral of surgery (n:5), loss to follow-up (n:5) and assessed as high anaesthetic risk (n:4). IO-PTH measurements performed on 28 patients indicated surgical success in 100%, based on Miami criteria. Histology confirmed adenoma in 88.1%, hyperplasia in 7.1% and carcinoma in 4.8%. Post-operative hypocalcaemia developed in 30 patients (35.7%), of whom, 14 developed hungry bone syndrome (HBS). In multivariate analysis, significant risk factors associated with HBS included male sex (OR 7.01; 95% CI 1.28, 38.39; p 0.025) and elevated pre-operative PTH (OR 1.01; 95% CI 1.00, 1.02; p 0.008). CONCLUSIONS: The proportion of asymptomatic PHPT has increased at this centre over the past decade but symptomatic disease remains the dominant presentation. Parathyroidectomy is curative in the majority of patients. IO-PTH monitoring is valuable in ensuring successful surgery.

Persistent hypercalcaemia associated with two pathogenic variants in the CYP24A1 gene and a parathyroid adenoma-a case report and review.

Introduction: 24-Hydroxylase, encoded by the CYP24A1 gene, is a crucial enzyme involved in the catabolism of vitamin D. Loss-of-function mutations in CYP24A1 result in PTH-independent hypercalcaemia with high levels of 1,25(OH)2D3. The variety of clinical manifestations depends on age, and underlying genetic predisposition mutations can lead to fatal infantile hypercalcaemia among neonates, whereas adult symptoms are usually mild. Aim of the study: We report a rare case of an adult with primary hyperparathyroidism and loss-of-function mutations in the CYP24A1 gene and a review of similar cases. Case presentation: We report the case of a 58-year-old woman diagnosed initially with primary hyperparathyroidism. Preoperatively, the suspected mass adjoining the upper pole of the left lobe of the thyroid gland was found via ultrasonography and confirmed by 99mTc scintigraphy and biopsy as the parathyroid gland. The patient underwent parathyroidectomy (a histopathology report revealed parathyroid adenoma), which led to normocalcaemia. After 10 months, vitamin D supplementation was introduced due to deficiency, and the calcium level remained within the reference range. Two years later, biochemical tests showed recurrence of hypercalcaemia with suppressed parathyroid hormone levels and elevated 1,25(OH)2D3 concentrations. Further investigation excluded the most common causes of PTH-independent hypercalcaemia, such as granulomatous disease, malignancy, and vitamin D intoxication. Subsequently, vitamin D metabolites were measured using LC-MS/MS, which revealed high levels of 25(OH)D3, low levels of 24,25(OH)2D3 and elevated 25(OH)2D3/24,25(OH)2D3 ratios, suggesting a defect in vitamin D catabolism. Molecular analysis of the CYP24A1 gene using the NGS technique revealed two pathogenic variants: p.(Arg396Trp) and p.(Glu143del) (rs114368325 and rs777676129, respectively). Conclusions: The diagnostic process for hypercalcaemia becomes complicated when multiple causes of hypercalcaemia coexist. The measurement of vitamin D metabolites using LC-MS/MS may help to identify carriers of CYP24A1 mutations. Subsequent molecular testing may contribute to establishing the exact frequency of pathogenic variants of the CYP24A1 gene and introducing personalized treatment.

Hyperparathyroidism Jaw Tumor Syndrome, an Unforeseen Diagnosis.

Asymptomatic primary hyperparathyroidism (PHPT) is often missed in developing nations due to limited formal healthcare exposure and biochemical screening programs. Many patients are thus only diagnosed once symptomatic. We present a 32-year-old female who developed bony protrusions in her jaw during pregnancy, resulting in a stillbirth. Three months later, during a dental consultation for worsening toothache, jaw abnormalities were detected. Radiological studies revealed bilateral mandibular radiolucent lesions, and bone biopsy confirmed histological features consistent with a brown tumor. These findings raised concerns about underlying PHPT, which was confirmed with a markedly elevated parathyroid hormone level in the presence of significant hypercalcemia. Further examination revealed impaired renal function, normal urine calcium excretion, and bilateral nephrocalcinosis. Low bone mineral density was measured with dual-energy X-ray absorptiometry, and conventional radiology identified additional low-density bony lesions in keeping with brown tumors. A parathyroid MIBI confirmed the presence of a singular parathyroid adenoma. A vague but possible family history, the patient's young age, and the severe renal and skeletal involvement prompted genetic testing. A cell division cycle 73 (CDC73) pathogenic variant, in keeping with primary hyperparathyroidism jaw tumor syndrome, was identified.

Long-Term Calcium Monitoring Post Parathyroidectomy for Primary Hyperparathyroidism.

BACKGROUND:  Cure rates following parathyroidectomy for primary hyperparathyroidism are excellent, with well-documented low short-term recurrence rates of hypercalcaemia. Rates of long-term recurrence have been investigated to a lesser extent, but recent studies have reported higher than anticipated rates. This study sought to evaluate recurrence rates at more than four years post seemingly corrective surgery and depending on the findings, propose whether recommendations of annual calcium monitoring post-parathyroidectomy are appropriate based on the limited data available at the time of formulating guidelines. METHODS: Fifty-two sequential parathyroidectomies for primary hyperparathyroidism from 2014-2016 from a single unit were retrospectively followed up with serum calcium levels. A hospital computer system was used to collect data on pre-operative, immediate post-operative and most recent follow-up calcium levels. Patients were excluded if there was no minimum of 48 months between the operation date and most recent calcium. Recurrence was defined as hypercalcaemia more than six months after eucalcaemia post-parathyroidectomy. RESULTS: Of the 52 cases analysed, two were lost to long-term follow-up, two patients died during the follow-up period while 10 did not meet the inclusion criteria of at least 48 months follow-up. This resulted in a cohort of 38 patients (mean age 66.4 years, 78.9% female). The median follow-up of 73.17 months (range 48.77-95.47 months) demonstrated a hypercalcaemia recurrence of 5.26% (2/38 patients). These cases were due to misdiagnosed parathyroid hyperplasia as opposed to suspected adenoma. Therefore, the long-term cure rate was 94.74% (36/38 patients). CONCLUSION: These findings support the high cure rates and low recurrence rates of the numerous short-term studies already performed despite a longer follow-up period. This is in contrast to recent series which have documented a higher recurrence in the long-term. This study would, therefore, suggests recommendations of annual calcium monitoring are excessive and that less frequent calcium monitoring is necessary in the first few years post-operation. However, the 5.26% recurrence rate in this study is not insignificant and follow-up is still paramount. Therefore, following the initial post-operative assessment, the authors propose a follow-up at the five-year mark and an annual continuation from this point forward due to the evidenced delayed recurrence of hypercalcaemia.

Kidney manifestations of sarcoidosis.

Renal involvement is a clinically relevant organ manifestation of sarcoidosis, leading to increased morbidity and complications. Although the exact incidence remains unknown, renal disease is likely to occur in up to one third of all sarcoidosis patients. Every patient with newly diagnosed sarcoidosis should receive a renal work-up and screening for disrupted calcium metabolism. Amid various forms of glomerulonephritis, granulomatous interstitial nephritis is the most common one, but it rarely leads to renal impairment. Histologically, granulomas can be absent. Nephrocalcinosis and nephrolithiasis are frequent forms when hypercalcaemia or hypercalciuria occur. Drugs used for treatment of systemic sarcoidosis can also cause renal damage. Due to its high heterogeneity, renal sarcoidosis can be difficult to treat. Glucocorticoids and various immunosuppressive treatments have been proven to be effective based on case series, but clinical trials are lacking. A treatment guideline for renal sarcoidosis is urgently needed. In this review article, we present an overview of the different forms of renal sarcoidosis and the diagnostic steps to confirm renal involvement; in addition, we provide insights on the management and available treatments. A better understanding regarding the pathogenesis of sarcoidosis is the key for the development of more specific, targeted therapies.

Pneumocystis jirovecii pneumonia presenting with severe, refractory hypercalcaemia in an immunosuppressed renal transplant patient: Review of the literature and novel biochemical insights.

Pneumocystis jirovecii pneumonia (PJP) is a rare but serious complication of immunosuppression post-solid organ transplantation. We present a case of refractory, severe hypercalcaemia due to PJP in a renal transplant recipient. Treatment of PJP led to normalisation of the patient's calcium levels, and clinical improvement. To further explore the proposed calcitriol-driven mechanism leading to hypercalcaemia in PJP, we performed biochemical analysis on pre- and post-treatment serum and bronchoalveolar lavage sample at the time of PJP diagnosis. We confirmed high circulating and pulmonary levels of calcitriol in acute, untreated PJP with severe hypercalcaemia. PJP treatment led to reduction of circulating calcitriol to within normal range. We present this case, together with a literature review of similar reported cases, and the novel biochemical evidence supporting extra-renal production of calcitriol by activated pulmonary macrophages as the mechanism underpinning hypercalcaemia in PJP.

Hyperparathyroidism and Peripheral Arterial Disease.

Primary hyperparathyroidism (PHPT) is presented in various forms, including classic PHPT, characterised by increased parathyroid hormone (PTH) secretion, normohormonal PHPT, and normocalcaemic PHPT. Secondary hyperparathyroidism is characterised by increased PTH secretion triggered by factors such as vitamin D deficiency and kidney failure. This review aims to discuss the involvement of hyperparathyroidism (HPT) in atherosclerosis, including peripheral arterial disease (PAD). The increased level of PTH is involved in developing subclinical and overt vascular diseases, encompassing endothelial dysfunction, vascular stiffness, hypertension, and coronary and peripheral arterial diseases. It has been consistently associated with an augmented risk of cardiovascular morbidity and mortality, independent of classical risk factors for atherosclerosis. Chronic hypercalcemia associated with increased levels of PTH contributes to the development of calcification of vessel walls and atherosclerotic plaques. Vascular calcification can occur in the intima or media of the arterial wall and is associated with stiffness of peripheral arteries, which the formation of atherosclerotic plaques and narrowing of the vessel lumen can follow. For treating hyperparathyroidism, particularly SHPT, calcimimetics, novel phosphorus binders and novel vitamin D receptor activators are used. However, they are ineffective in severe PHPT. Therefore, parathyroidectomy remains the primary therapeutic option of PHPT.

Inherited non-FGF23-mediated phosphaturic disorders: A kidney-centric review.

Phosphate is freely filtered by the glomerulus and reabsorbed exclusively in the proximal tubule by two key transporters, NaPiIIA and NaPiIIC, encoded by SLC34A1 and SLC34A3, respectively. Regulation of these transporters occurs primarily through the hormone FGF23 and, to a lesser degree, PTH. Consequently, inherited non-FGF23 mediated phosphaturic disorders are due to generalised proximal tubular dysfunction, loss-of-function variants in SLC34A1 or SLC34A3 or excess PTH signalling. The corresponding disorders are Renal Fanconi Syndrome, Infantile Hypercalcaemia type 2, Hereditary Hypophosphataemic Rickets with Hypercalciuria and Familial Hyperparathyroidism. Several inherited forms of Fanconi renotubular syndrome (FRTS) have also been described with the underlying genes encoding for GATM, EHHADH, HNF4A and NDUFAF6. Here, we will review their pathophysiology, clinical manifestations and the implications for treatment from a kidney-centric perspective, focussing on those disorders caused by dysfunction of renal phosphate transporters. Moreover, we will highlight specific genetic aspects, as the availability of large population genetic databases has raised doubts about some of the originally proposed gene-disease associations concerning phosphate transporters or their associated proteins.

Association between total hypercalcaemia and iliosacral lymph node metastasis in dogs diagnosed with anal sac adenocarcinoma using abdominal ultrasonography.

BACKGROUND: Anal sac adenocarcinoma (ASACA) in dogs is a malignant perianal tumour that often metastasizes to the iliosacral lymph nodes. Additionally, this tumour can be associated with hypercalcemia of malignancy. To date, no study has looked at the association between increased blood calcium levels and suspected or confirmed lymph node metastasis as a primary objective. OBJECTIVE: The objective of this study was to determine if increased total serum calcium level is associated with iliosacral lymph node metastasis in dogs diagnosed with ASACA. METHODS: Medical records of a single referral hospital were searched to identify dogs examined between 2011 and 2021 that had a diagnosis of ASACA via cytology or histopathology. Only dogs that had serum total calcium recorded and abdominal ultrasound were included in the study. All images were reviewed by a board-certified radiologist blinded to any patient identifiers. RESULTS: Of the 58 dogs, 33% (19/58) had total hypercalcaemia, and of these, 68% had confirmed or suspected iliosacral lymph node metastasis. Total hypercalcaemia was significantly associated with confirmed or suspected iliosacral lymph node metastasis (p < 0.01). However, 46% (11/24) of dogs with confirmed or suspected iliosacral lymph node metastasis were normocalcaemic. CONCLUSIONS: Based on these results, it is suggested that while the presence of total hypercalcaemia may increase the likelihood of concurrent lymph node metastasis, total hypercalcaemia alone cannot be used as a screening tool for lymph node metastasis. Dogs diagnosed with ASACA should undergo full staging regardless of total serum calcium values.

Parathyroid Carcinoma Presenting as Recurrent Primary Hyperparathyroidism and Neck Mass: A Case Report.

Parathyroid carcinoma is a rare endocrine neoplasm that accounts for <1% of cases of primary hyperparathyroidism. The management of parathyroid carcinoma is a challenge due to the high rate of local recurrence of the tumour. We report the case of a middle-aged north Indian woman who presented with recurrent primary hyperparathyroidism due to parathyroid carcinoma. She presented with a recurrent palpable hard neck mass and underwent radical dissection of the neck six times. At the time of writing this report, she was referred for external beam radiotherapy to the neck. Parathyroid carcinoma is a rare malignancy with an indolent but tenacious course. Complete resection at the time of initial surgery determines the prognosis of the neoplasm. Chemotherapy and radiotherapy are usually ineffective. Hypercalcaemia needs to be aggressively managed. A multidisciplinary team is required to effectively manage parathyroid carcinoma.

Thiazide diuretics and primary hyperparathyroidism.

Thiazide diuretics exert a natriuretic and diuretic effect by inhibiting sodium reabsorption in the distal convoluted tubule. Furthermore, thiazide diuretics affect renal calcium handling by increasing calcium reabsorption, leading to hypocalciuria. The effect that thiazide diuretics exert on parathyroid hormone secretion is controversial. Some studies found parathyroid hormone levels were suppressed with the use of thiazide diuretics, while others found that thiazides were associated with initial parathyroid hormone suppression followed by raised parathyroid hormone levels. This makes the relationship between thiazide diuretics and primary hyperparathyroidism interesting. If a patient is taking thiazide diuretics, this may make it harder to establish the aetiology of hypercalcaemia and may unmask normocalcaemic or mild primary hyperparathyroidism. Thiazide diuretics may have a beneficial role in the diagnosis of patients with concomitant hyperparathyroidism and hypercalciuria by distinguishing secondary hyperparathyroidism caused by hypercalciuria from normocalcaemic primary hyperparathyroidism. In addition, thiazide diuretics may have a role in managing patients with primary hyperparathyroidism who have an indication for parathyroidectomy in view of significant hypercalciuria, but are unfit for surgery.

From acute hypercalcaemia to post-parathyroidectomy hungry bone syndrome in a patient with primary hyperparathyroidism-associated brown tumours.

Not required for Clinical Vignette.

[A rare cause of kidney injury: vitamin D3 intoxication]. / A vesekárosodás ritka oka: D3-vitamin-intoxikáció.

The beneficial effects of vitamin D3 treatment are known, and its side effects are documented. In connection with the case presentation, we would like to sum up the dangers of excessive vitamin D supplementation, and to draw attention to the shortcomings experienced in everyday medical practice. We discuss the tests required to create a diagnosis of vitamin D intoxication, the differential diagnosis, and present the possible treatment strategies. A 57-year-old female patient was admitted to hospital in November 2020 due to complaints of nausea, vomiting, diarrhea and general weakness. Upon admission, laboratory tests confirmed new-onset kidney damage (eGFR 38 mL/min/1.73 m2), calcium metabolism was not checked. During non-invasive investigations, urinary sediment results showed leukocyturia and non-nephrotic proteinuria, but no clear underlying cause was found. Nephrology consultation suggested acute tubular injury, kidney biopsy was performed, immune serology and serum protein electrophoresis tests were ordered. Despite conservative treatment, her kidney function deteriorated further (eGFR 32 mL/d/1.73 m2). The patient arrived at our department in December 2020 with histological results in progress. Laboratory tests taken on arrival confirmed severe hypercalcemia (tCa 3.22 mmol/L, iCa 1.74 mmol/L), and kidney function was stable (eGFR 33 mL/p/1.73 m2). Intact parathyroid hormone level was below the normal range (0.54 pmol/L), 25-OH-vitamin D level was extremely high (1106.2 nmol/L). The patient then admitted that in October 2020, she received a course of "megadose" parenteral vitamin D, but she could not recall the exact dosage nor wanted to mention the department administering the treatment. We diagnosed vitamin D intoxication. Intravenous saline, furosemide and calcitonin treatment was started. The result of the treatment: serum calcium level normalized (2.52 mmol/L), and kidney functions improved (eGFR 54 mL/p/1.73 m2). Vitamin D treatment was stopped. The patients' serum tCa and vitamin D levels normalized by February 2021, and her kidney functions improved (tCa 2.54 mmol/L, 25-OH-vitamin D 125.0 ng/mL, eGFR 72 mL/p/1.73 m2). Kidney biopsy confirmed the presence of acute tubular necrosis. Granulomatous diseases and multiple myeloma were excluded. The symptoms of vitamin D intoxication are non-specific and varied, each case presents a differential diagnostic challenge. Orv Hetil. 2023; 164(47): 1871-1876.

Outcomes of Surgical Management for Parathyroid Adenomas.

Aim: Descriptive analysis of patients undergoing parathyroid adenoma surgery at a tertiary care hospital. Methodology: Patients with parathyroid adenoma operated from January 2016 to December 2020. Serum calcium and PTH were used to establish the diagnosis. Ultrasonography (USG) studies localized the adenoma. NIH criteria was used for decision regarding surgery. Patients were analyzed with regards to pre operative localization, biochemical monitoring and other outcomes. Results: Of the 15 eligible patients, all were symptomatic, with myalgia (34%) being the commonest symptom. Rome criteria confirmed the adequacy of the procedure by measuring intra operative drop in PTH. Average decrease in serum PTH level was 69.9% and serum calcium was 20.6% after excision of adenoma. The average size of excised adenoma was 2.5 cm. There were no post operative complications and all patients were normocalcemic on follow up. Conclusion: Parathyroidectomy is a simple, safe and effective solution that reduces the morbidity of symptomatic primary hyperparathyroidism patients. Pre operative localization studies affirm the diagnosis and intra operative biochemical confirmation clinches the adequacy of resection.

Sarcoidosis presenting as a loss of weight with preserved appetite.

Sarcoidosis is a multisystem inflammatory disorder of unknown aetiology affecting a wide range of organs and is characterised by the presence of noncaseating granulomas. It has rarely been reported in Sri Lanka. This case describes a 36-year-old male presenting with a loss of weight despite a preserved appetite. He had evidence of sarcoidosis with pulmonary, lymph node, eye, hepatosplenomegaly, thyroid and parotid gland involvement with hypercalcaemia. He was successfully treated with glucocorticoids.

Treatment of hypercalcaemia of malignancy in adults.

Hypercalcaemia of malignancy (HCM) is a common metabolic complication of advanced malignancies with a prevalence varying from 2-30%, depending on cancer type and disease stage. HCM is associated with impaired quality of life, increased risk of hospitalisation and limited survival. Evidence-based guidelines for management of HCM have been lacking to date, despite its prevalence and detrimental impact. This concise guidance highlights key recommendations from the recent Endocrine Society Clinical Practice Guidelines on Treatment of Hypercalcaemia of Malignancy in Adults, published in December 2022. A systematic review and meta-analysis was commissioned to support the guideline development process. Key suggestions include the use of denosumab in preference to intravenous bisphosphonates as first-line treatment for HCM and the use of denosumab in cases of recurrent or refractory HCM in patients previously treated with intravenous bisphosphonates. The guideline also identifies priority areas for future research.