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Open access

Reversibility in male idiopathic osteoporosis possible

Ijaz S Jamall, Michael C Ullery, Massimiliano Rocchietti March, Elisa Pignatti, Vincenzo Rochira, and Björn L D M Brücher

Summary

A 44-year-old athletic man presented in 2009 with severe low back pain. Dual-energy x-ray absorptiometry revealed severe osteoporosis; serum testosterone was 189 ng/dL while serum estradiol (E2) measured by liquid chromatography/mass spectrometry was 8 pg/mL. DNA was extracted and sequenced from a blood sample from the patient since his maternal first cousin also had low bone mass and both patients were screened for aromatase dysfunction by PCR analysis for the CYP19A1 gene, which encodes aromatase. No known pathologic mutations were observed in the coding exons, but novel single nucleotide polymorphisms were detected both in the proband and in his cousin. Treatment with topical testosterone started in August 2010. Over the next 8 years, testosterone dosage was varied and switched from topical gel to injections and maintained on depo-injections of testosterone at about 60 mg once per week. Re-examination in March 2012 included a brain MRI to exclude pituitary lesions; hyperparathyroidism was ruled out (normal serum parathyroid hormone, calcium, and calcium to phosphorous ratio) and celiac disease was excluded (negative transglutaminase antibodies). Follow-up in October 2018 showed improved bone mineral density of the lumbar spine by 29% and of the left femoral hip by 15% compared to baseline measurements. This reveals the importance of measuring serum E2 for making the correct diagnosis, as well as for monitoring a therapeutic effect. Herein, we propose treatment of male osteoporosis where serum E2 levels are below about 20 pg/mL with testosterone to reverse osteoporosis.

Learning points

  • Estrogen deficiency in the diagnosis of male idiopathic osteoporosis.

  • Importance of serum estradiol in male osteoporosis.

  • Role of polymorphisms in aromatase gene on bone health.

  • Reversal of osteoporosis.

  • Tailored testosterone treatment for bone health.

DOI:
https://doi.org/10.1530/EDM-22-0407
Volume 2023: Issue 2
Open access

Tenofovir-induced hypophosphatemic osteomalacia: how do bone mineral density, trabecular bone score and proximal hip geometry change with treatment?

Aneez Joseph, Kripa Elizabeth Cherian, Nitin Kapoor, and Thomas V Paul

Summary

Tenofovir-induced osteomalacia secondary to proximal renal tubular dysfunction is not an uncommon complication known to occur. A 46-year-old woman was referred for the evaluation of osteoporosis which was diagnosed elsewhere. She had polyarthralgia, bony pains and proximal muscle weakness of 1 year duration. She was diagnosed to have HIV infection and was on antiretroviral therapy that consisted of tenofovir, lamivudine and efavirenz for the past 12 years. She had attained menopause 5 years back. On examination, she had bone tenderness, proximal myopathy and painful restriction of movement of her lower limbs. Investigations showed features of renal tubular acidosis, hypophosphatemia and raised alkaline phosphatase that were suggestive of osteomalacia. X-ray of the pelvis showed diffuse osteopenia and an MRI of the pelvis done showed multiple insufficiency fractures involving the head of femur on both sides. Following this, her tenofovir-based regimen was changed to abacavir, efavirenz and lamivudine with addition of neutral phosphate supplements and calcitriol. On follow-up after 6 months, she had significant improvement in her symptoms as well as in the bone mineral density at the lumbar spine (33.2%), femoral neck (27.6%), trabecular bone score (13.2%) and reduction in the buckling ratio at the narrow neck (6.3%), inter-trochanteric region (34%) and femoral shaft (28.8%). Tenofovir-induced osteomalacia is encountered in individuals on prolonged treatment with tenofovir. Treatment consists of changing to a non-tenofovir-based regimen, as well as supplementation of phosphate and calcitriol. Treatment results in remarkable improvement in symptoms and most densitometric indices.

Learning points

  • Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI) and is a major drug in the treatment of retroviral and hepatitis B infections.

  • Tenofovir-related hypophosphatemic osteomalacia is related to proximal tubulopathy and is not an uncommon occurrence.

  • Treatment mandates changing to a non-tenofovir-based regimen with supplementation of neutral phosphate and calcitriol.

  • Treatment results in a significant improvement in bone mineral density, trabecular bone score and hip geometric parameters.

DOI:
https://doi.org/10.1530/EDM-22-0259
Volume 2023: Issue 1
Open access

Effect of early dose increase of evocalcet for intractable hypercalcemia caused by parathyroid carcinoma

Azusa Morishita, Yasuo Hozumi, Hiroaki Ishii, Yukio Hokazono, Clovis Manuel Yosei Kikuchi, Megumi Shimasaki, Mikiko Itaya, Masaharu Oura, Ken Kuriki, Akira Hishida, and George Seki

Summary

Hypercalcemia due to parathyroid carcinoma (PC) is safely and quickly controlled with rapidly increasing evocalcet doses. Most parathyroid carcinomas are detected because of hypercalcemia due to primary hyperparathyroidism (PHPT). Hypercalcemia becomes more severe in patients with PC than those with parathyroid adenoma or hyperplasia. Hypercalcemia often causes renal dysfunction, gastrointestinal symptoms, and psychiatric symptoms. Consequently, the serum calcium level needs to be promptly corrected. Here, we report a case of PC with remarkably persistent hypercalcemia, which we safely and quickly controlled with rapidly increasing evocalcet doses. A 77-year-old female presented with renal dysfunction. Her serum calcium (Ca) and intact parathyroid hormone serum levels were 13.9 mg/dL and 1.074 pg/mL, respectively. Her renal function worsened because of hypercalcemia due to PHPT. Technetium-99 m methoxy-isobutyl-isonitrile parathyroid scintigraphic examination revealed an accumulation below the right thyroid lobe. CT examination showed a 35-mm mass. Hypercalcemia needed to be immediately corrected because of the patient’s worsening renal function. Evocalcet treatment at a gradually increasing dose of up to 20 mg over 3 weeks allowed her serum Ca level to be maintained below 11 mg/dL. Only mild nausea was observed at the beginning of the treatment. The mass was suspected as PC because the hypercalcemia was refractory to high-dose evocalcet. The patient was treated with parathyroidectomy and ipsilateral thyroidectomy. PC was diagnosed based on the pathological findings of capsular and venous invasion. The patient’s renal function improved and surgery could be safely performed by promptly correcting hypercalcemia.

Learning points

  • Hypercalcemia due to parathyroid carcinoma (PC) is often more severe than that caused by parathyroid adenoma or hyperplasia.

  • PC is a rare disease, but it should be considered if the patient has intractable hypercalcemia due to primary hyperparathyroidism (PHPT).

  • Evocalcet, which is used to treat hypercalcemia due to PHPT, does not interact with P450 (CYP) and causes few side effects.

  • Complications, including renal dysfunction, were improved and the surgery could be safely performed by promptly correcting hypercalcemia.

  • PC has a high recurrence rate. En-block excision is necessary when PC is suspected.

DOI:
https://doi.org/10.1530/EDM-22-0269
Volume 2023: Issue 1
Open access

Treating ‘osteoporosis’: a near miss in an unusual case of FGF-23-mediated hypophosphataemic osteomalacia

Mike Lin and Kirtan Ganda

Summary

We present the case of a 60-year-old female who developed repeated atraumatic stress fractures. She was initially diagnosed with osteoporosis based on her dual-energy X-ray absorptiometry (DXA) scan bone mineral density (BMD) T-scores and started on denosumab therapy. Secondary osteoporosis screen revealed abnormal myeloma screen and low serum phosphate levels. It was thought that the patient had multiple myeloma with associated Fanconi-related tubular dysfunction. However, fibroblast growth factor-23 (FGF-23) levels were grossly elevated, making Fanconi syndrome unlikely. The patient was subsequently diagnosed with two separate conditions, namely cardiac amyloid light-chain (AL) amyloidosis and FGF-23-related hypophosphataemia, likely due to tumour-induced osteomalacia. This case highlights the importance of excluding osteomalacia as a cause of low BMD and checking FGF-23 levels in the workup for hypophosphataemia.

Learning Points

  • Tumour-induced osteomalacia is a difficult diagnosis as the tumour is often small and slow growing. Imaging may fail to identify a tumour, and treatment therefore consists of calcitriol and phosphate replacement.

  • Tumour-induced osteomalacia should be suspected in the adult presenting with new-onset hypophosphataemia, elevated FGF-23 levels and isolated renal phosphate wasting.

  • Serum phosphate is not part of the routine chemistry panels. Routinely checking phosphate levels prior to initiating antiresorptive therapy is warranted.

  • DXA cannot distinguish low bone mineral density due to osteoporosis from osteomalacia. Antiresorptive therapy should be avoided in osteomalacia due to the risk of clinical and radiographic deterioration.

DOI:
https://doi.org/10.1530/EDM-22-0300
Volume 2022: Issue 1
Open access

Hypercalcemia in the setting of HTLV-1 infection and a normal PTHrP level

Keerthana Haridas

Summary

Human T-cell lymphotropic virus-1 (HTLV-1) causes adult T-cell leukemia and lymphoma (ATLL) and is a rare but important cause of hypercalcemia. A 53-year-old male with HTLV-1-associated myelopathy presented with acute on chronic bilateral lower extremity weakness and numbness. Initial blood work revealed hypercalcemia with corrected calcium of 16.2 mg/dL (8.5–11.5) with normal levels of phosphorus and alkaline phosphatase. Workup for hypercalcemia revealed parathyroid hormone (PTH) of 14 pg/mL (10–65), 25 hydroxy vitamin D at 19.6 ng/mL (30–100), 1,25 dihydroxy vitamin D at 6.7 pg/mL (19.9–79.3), thyroid-stimulating hormone of 1.265 μIU/mL (0.5–5), undetectable PTH-related protein (PTHrP) and lactate dehydrogenase of 433 U/L (100–220). The urine calcium creatinine ratio was 0.388. Reverse transcriptase PCR was positive for HTLV-1 and negative for HTLV-2. Peripheral blood flow cytometry and lymph node biopsy confirmed ATLL. He received treatment with fluids, calcitonin and denosumab after which serum calcium levels fell (nadir: 7.7 mg/dL) and then normalized. Humoral hypercalcemia in this setting is mediated by receptor activator of nuclear factor-kappa B ligand (RANKL), PTHrP and other cytokines. PTHrP levels depend on levels of the TAX gene product, cell type and lymphocyte-specific factors. Thus, a low level, like in our patient, does not rule out HTLV-1 infection/ATLL as the cause of hypercalcemia. Hypercalcemia is known to be responsive to monoclonal antibodies against RANKL given the compound’s role in mediating hypercalcemia in these cases.

Learning points

  • Human T-cell lymphotropic virus-1 infection and adult T-cell leukemia and lymphoma are associated with high rates of hypercalcemia and hypercalcemic crises.

  • Hypercalcemia in these cases is mediated by osteoclastic bone resorption carried out by several agents including receptor activator of nuclear factor-kappa B ligand, parathyroid hormone-related protein (PTHrP), macrophage inflammatory protein 1 alpha, interleukins, etc. A normal PTHRrP does not rule out humoral hypercalcemia of malignancy in this setting, as indicated by this case.

  • Hypercalcemia in such settings is highly responsive to monoclonal antibodies against RANKL given the role the ligand plays in resorptive hypercalcemia.

DOI:
https://doi.org/10.1530/EDM-22-0299
Volume 2022: Issue 1
Open access

Management of severe and symptomatic primary hyperparathyroidism in the first trimester of unplanned pregnancy

Adele J Beck, Venkat M Reddy, Tom Sulkin, and Duncan Browne

Summary

Primary hyperparathyroidism (PHP) is the most common aetiology for hypercalcaemia. The incidence of PHP in pregnant women is reported to be 8/100 000 population/year. It presents a threat to the health of both mother (hyperemesis, nephrolithiasis) and fetus (fetal death, congenital malformations, and neonatal severe hypocalcaemia-induced tetany). However, there is a lack of clear guidance on the management of primary hyperparathyroidism in pregnancy. In this study, we describe the case of a 26-year-old female patient who presented with severe hypercalcaemia secondary to PHP and underwent successful parathyroid adenectomy under local anaesthesia.

Learning points

  • Primary hyperparathyroidism is a rare complication in pregnancy, but the consequences for mother and fetus can be severe.

  • A perceived risk of general anaesthesia to the fetus in the first trimester has resulted in a general consensus to delay parathyroid surgery to the second trimester when possible – although the increased risk of fetal loss may occur before planned surgery.

  • If the patient presents with severe or symptomatic hypercalcaemia, minimally invasive surgery under local anaesthetic should be considered regardless of the gestational age of the pregnancy.

DOI:
https://doi.org/10.1530/EDM-21-0203
Volume 2022: Issue 1
Open access

Bisphosphonate-induced atypical femoral fracture in tandem: long-term follow-up is warranted

Mohammed Anwar Hussain, Aneez Joseph, Vinoo Mathew Cherian, Alok Srivastava, Kripa Elizabeth Cherian, Nitin Kapoor, and Thomas Vizhalil Paul

Summary

Although bisphosphonates (BPs) are mainly used for the treatment of osteoporosis and are generally safe, long-term use and more dosage as utilised in malignant conditions may be associated with the rare adverse event of an atypical femoral fracture (AFF). Occasionally, the risk of developing an AFF persists long after BPs are withdrawn. A 39-year-old woman who underwent chemotherapy and an autologous stem cell transplantation for multiple myeloma presented to us with history of pain in the left thigh. She had received multiple doses of oral and parenteral BPs for about 10 years in view of the underlying myeloma with osteoporosis. Her investigations showed a suppressed CTX of 192 pg/mL, and radiograph of pelvis displayed thickened cortices with beaking of the left femoral shaft, which was suggestive of an AFF. Following discontinuation of BPs, she underwent prophylactic intra-medullary nailing with which her symptoms improved. Five years later, she presented with similar complaints on the right side. Investigations showed that her bone turnover continued to be suppressed with Cross linked C- Telopeptide of type 1 collagen (CTX) of 165 pg/mL and an X-ray done showed AFF on the right side despite being off BPs. A second intra-medullary nailing was done and on follow-up, she has been symptom-free and independent in her daily activities. Discontinuation of BPs may not prevent the incident second AFF and, therefore, thus warranting long-term follow-up.

Learning points

  • Regular screening and follow-up of patients who receive long-term bisphosphonate (BP) therapy should be done.

  • Discontinuation of BPs does not preclude the possibility of repeated occurrence of a second AFF.

  • Long-term BP therapy warrants regular monitoring and follow-up should an AFF occur

DOI:
https://doi.org/10.1530/EDM-22-0249
Volume 2022: Issue 1
Open access

Another case of milk–alkali syndrome or a learning opportunity?

Sophie Bondje, Camilla Barnes, and Felicity Kaplan

Summary

Milk–alkali syndrome (MAS) is a triad of hypercalcaemia, metabolic alkalosis and renal insufficiency. In this study, we present a case of milk–alkali syndrome secondary to concurrent use of over-the-counter (OTC) calcium carbonate-containing antacid tablets (Rennie®) for dyspepsia and calcium carbonate with vitamin D3 (Adcal D3) for osteoporosis. A 72-year-old woman presented with a 2-day history of nausea, vomiting, epigastric pain, constipation, lethargy and mild delirium. Past medical history included osteoporosis treated with daily Adcal D3. Initial blood tests showed elevated serum-adjusted calcium of 3.77 mmol/L (normal range, 2.2–2.6) and creatinine of 292 µmol/L (45–84) from a baseline of 84. This was corrected with i.v. pamidronate and i.v. fluids. She developed asymptomatic hypocalcaemia and rebound hyperparathyroidism. Myeloma screen, vasculitis screen and serum angiotensin-converting enzyme (ACE) were normal, while the CT of the chest, abdomen and pelvis showed renal stones but no malignancy. A bone marrow biopsy showed no evidence of malignancy. Once the delirium resolved, we established that prior to admission, she had been excessively self-medicating with over-the-counter antacids (Rennie®) as required for epigastric pain. The increasing use of calcium preparations for the management of osteoporosis in addition to easily available OTC dyspepsia preparations has made MAS the third most common cause of hypercalcaemia hospitalisations. Educating patients and healthcare professionals on the risks associated with these seemingly safe medications is required. Appropriate warning labels on both calcium preparations used in the management of osteoporosis and OTC calcium-containing preparations would prevent further similar cases and unnecessary morbidity and hospital admission.

Learning points

What is known?

  • An association between high-dose calcium supplementation and hypercalcaemia crisis has been seen in case studies.

  • After as little as 1 week of excessive calcium carbonate ingestion, patients can present with symptomatic hypercalcemia, acute renal failure and metabolic alkalosis ().

  • Women aged 50 and younger need 1 g of calcium per day, while aged 51 and older need 1.2 g ().

  • Although the amount of calcium required for MAS is generally thought to be more than 4 g per day, there have been reports at intakes as low as 1.0–1.5 g per day in pre-existing risk factors including renal impairment ().

What this study adds?

  • The danger of excessive ingestion of antacid is not adequately highlighted to prescribers and patients.

  • Appropriate warning labels on OTC calcium-containing preparations could prevent unnecessary morbidity and hospital admission.

DOI:
https://doi.org/10.1530/EDM-21-0151
Volume 2022: Issue 1
Open access

An extremely rare case of calcinosis cutis in human Cushing’s disease

Najoua Rbiai, Ikram Mahroug, Nada Zizi, and Hanane Latrech

Summary

Cushing’s disease or pituitary adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome is considered a rare condition. It is caused by hypersecretion of the ACTH by a pituitary adenoma that ultimately induces endogenous hypercortisolism by stimulating the adrenal glands. It is responsible for significant morbidity and mortality. The clinical signs and symptoms of hypercortisolism are usually common and non-specific including obesity, moon face, hypertension, hirsutism and facial plethora. The association between Cushing’s disease and calcinosis cutis which is defined as dystrophic calcium deposition in the skin and subcutaneous tissues is extremely rare. To the best of our knowledge, it has never been described previously in humans, probably like a symptom or complication of chronic and severe hypercortisolism. In this paper, we report a case of a 30-year-old female diagnosed with Cushing’s disease and presented bilateral leg’s calcinosis cutis complicated with ulceration. The evolution was favorable and the complete cicatrization was obtained 12 months following the suppression of systemic glucocorticoid excess.

Learning points

  • Calcinosis cutis is common in autoimmune connective diseases. However, to our knowledge, it has never been reported in humans with Cushing’s disease.

  • Given the rarity of this association, the diagnostic approach to calcinosis cutis must exclude the other etiologies.

  • Calcinosis cutis is challenging to treat with no gold standard therapy. In our case, the use of the combination of colchicine and bisphosphonates does not significantly improve the patient’s outcomes. In fact, we suppose that without treating the endogenous hypercortisolism, the calcinosis cutis will not resolve.

DOI:
https://doi.org/10.1530/EDM-21-0113
Volume 2022: Issue 1
Open access

Immobilization-induced hypercalcemia in a patient with renal failure

Anand Gandhi, Mike Mortensen, Sonie Sunny, Pawarid Techathaveewat, Jerome Targovnik, and Mahmoud Alsayed

Summary

Immobilization-induced hypercalcemia is an uncommon cause of elevated calcium which is usually diagnosed following extensive systemic workup and exclusion of more common etiologies. Previously reported cases have largely described this phenomenon in adolescents and young adults a few weeks to months after the initial onset of immobilization. Metabolic workup tends to demonstrate hypercalcemia, hypercalciuria, and eventual osteoporosis. While the exact mechanism remains largely unclear, a dysregulation between bone resorption and formation is central to the pathogenesis of this disease. Decreased mechanical loading from prolonged bedrest tends to increase osteoclast induced bone resorption while promoting osteocytes to secrete proteins such as sclerostin to reduce osteoblast mediated bone formation. We describe the case of an 18-year-old male who was admitted following intraabdominal trauma. He underwent extensive abdominal surgery including nephrectomy resulting in initiation of dialysis. After 6 months of hospitalization, the patient gradually began developing uptrending calcium levels. Imaging and laboratory workup were unremarkable for any PTH-mediated process, malignancy, thyroid disorder, adrenal disorder, or infection. Workup did reveal significant elevated bone turnover markers which in combination with the clinical history led the physicians to arrive at the diagnosis of immobilization induced hypercalcemia. In order to prevent decreased rates of bone loss, the patient was administered denosumab for treatment. Hypocalcemia followed treatment expectedly and was repleted with supplementation via the patient’s total parenteral nutrition.

Learning points

  • Immobilization-induced hypercalcemia should remain as a differential diagnosis of patients with prolonged hospitalizations with hypercalcemia.

  • Extensive workup of common etiologies of hypercalcemia should be considered prior to arriving at this diagnosis.

  • Denosumab, while off-label for this usage, offers an effective treatment option for immobilization-induced hypercalcemia though it carries a risk of hypocalcemia especially among patients with renal disease.

DOI:
https://doi.org/10.1530/EDM-21-0086
Volume 2021: Issue 1