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Ministry of National Guard – Health Affairs, Riyadh, Saudi Arabia
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Department of Paediatrics, Endocrine Division, Jeddah, Saudi Arabia
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Ministry of National Guard – Health Affairs, Riyadh, Saudi Arabia
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Ministry of National Guard – Health Affairs, Riyadh, Saudi Arabia
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Faculty of medicine, Sohag University, Egypt
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Summary
X-linked hypophosphatemic rickets (XLH), the most prevalent form of inherited hypophosphatemic rickets, is caused by loss-of-function mutations in the gene encoding phosphate-regulating endopeptidase homolog, X-linked (PHEX). This case series presents 14 cases of XLH from Gulf Cooperation Council (GCC) countries. The patients’ medical history, biochemical and radiological investigative findings, as well as treatment responses and side effects from both conventional and burosumab therapy, are described. Cases were aged 2–40 years at diagnosis. There were two male cases and 12 female cases. All cases were treated with conventional therapy which resulted in a lack of improvement in or worsening of the clinical signs and symptoms of rickets or biochemical parameters. Side effects of conventional therapy included nausea, diarrhea, abdominal pain, nephrocalcinosis, and hyperparathyroidism, which affected the patients’ quality of life and adherence to treatment. In the 10 patients treated with burosumab, there was a marked improvement in the biochemical markers of rickets, with a mean increase in serum phosphate of +0.56 mmol/L and tubular maximum phosphate reabsorption (TmP) to glomerular filtration rate (GFR) ratio (TmP/GFR) of +0.39 mmol/L at 12 months compared to baseline. Furthermore, a mean decrease in serum alkaline phosphatase (ALP) of −80.80 IU/L and parathyroid hormone (PTH) of −63.61 pmol/L at 12 months compared to baseline was observed in these patients. Additionally, patients treated with burosumab reported reduced pain, muscle weakness, and fatigue as well as the ability to lead more physically active lives with no significant side effects of treatment.
Learning points
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Conventional therapy resulted in a suboptimal response, with a lack of improvement of clinical signs and symptoms.
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Side effects of conventional therapy included nausea, diarrhea, abdominal pain, nephrocalcinosis, and hyperparathyroidism, which affected the patients’ quality of life and adherence to treatment.
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Burosumab demonstrated marked improvements in the biochemical markers of rickets, in addition to reducing pain, muscle weakness, and fatigue.
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There were no significant side effects associated with burosumab therapy.
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Summary
We present the first report of use of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) in a hypoparathyroid patient during early pregnancy and lactation. The patient developed postoperative hypoparathyroidism as a 28-year-old woman following total thyroidectomy for multinodular goiter. She was not well controlled with conventional therapy, and started rhPTH(1-84) in 2015 following its approval in the United States. She became pregnant in 2018 at age 40. She discontinued rhPTH(1-84) therapy at 5 weeks gestation but resumed in the postpartum period while breastfeeding. Her daughter’s serum calcium was borderline elevated at 8 days postpartum but within the normal range at 8 weeks postpartum. The patient stopped nursing at around 6 months postpartum. Her daughter is now at 4 years and 5 months of age and is healthy and meeting developmental milestones. She was again pregnant at 8 months postpartum from her first pregnancy, and she made an informed decision to continue parathyroid hormone. At 15 weeks gestation, rhPTH(1-84) was recalled in the United States due to issues with the delivery device, and she discontinued rhPTH(1-84) treatment and resumed calcium and calcitriol supplements. She gave birth to a baby boy at 39 weeks in January 2020. At 3 years and 2 months of age, he is overall healthy. Further data are needed regarding the safety of rhPTH(1-84) in pregnancy and lactation.
Learning points
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rhPTH(1-84) is approved for therapy of patients with hypoparathyroidism; however, there are no data regarding the safety of treatment during nursing and pregnancy.
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There are multiple alterations in mineral metabolism during normal pregnancy and lactation.
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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
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Hypercalcemia due to parathyroid carcinoma (PC) is often more severe than that caused by parathyroid adenoma or hyperplasia.
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PC is a rare disease, but it should be considered if the patient has intractable hypercalcemia due to primary hyperparathyroidism (PHPT).
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Evocalcet, which is used to treat hypercalcemia due to PHPT, does not interact with P450 (CYP) and causes few side effects.
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Complications, including renal dysfunction, were improved and the surgery could be safely performed by promptly correcting hypercalcemia.
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PC has a high recurrence rate. En-block excision is necessary when PC is suspected.
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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
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Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI) and is a major drug in the treatment of retroviral and hepatitis B infections.
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Tenofovir-related hypophosphatemic osteomalacia is related to proximal tubulopathy and is not an uncommon occurrence.
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Treatment mandates changing to a non-tenofovir-based regimen with supplementation of neutral phosphate and calcitriol.
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Treatment results in a significant improvement in bone mineral density, trabecular bone score and hip geometric parameters.
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The University of Sydney Concord Clinical School, Concord NSW, Australia.
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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
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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.
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Tumour-induced osteomalacia should be suspected in the adult presenting with new-onset hypophosphataemia, elevated FGF-23 levels and isolated renal phosphate wasting.
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Serum phosphate is not part of the routine chemistry panels. Routinely checking phosphate levels prior to initiating antiresorptive therapy is warranted.
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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.
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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
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Primary hyperparathyroidism is a rare complication in pregnancy, but the consequences for mother and fetus can be severe.
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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.
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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.
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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
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Regular screening and follow-up of patients who receive long-term bisphosphonate (BP) therapy should be done.
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Discontinuation of BPs does not preclude the possibility of repeated occurrence of a second AFF.
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Long-term BP therapy warrants regular monitoring and follow-up should an AFF occur
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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?
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An association between high-dose calcium supplementation and hypercalcaemia crisis has been seen in case studies.
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After as little as 1 week of excessive calcium carbonate ingestion, patients can present with symptomatic hypercalcemia, acute renal failure and metabolic alkalosis (1).
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Women aged 50 and younger need 1 g of calcium per day, while aged 51 and older need 1.2 g (1).
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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 (2).
What this study adds?
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The danger of excessive ingestion of antacid is not adequately highlighted to prescribers and patients.
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Appropriate warning labels on OTC calcium-containing preparations could prevent unnecessary morbidity and hospital admission.
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Department of Dermatology, Mohammed VI Hospital, Faculty of Medicine and Pharmacy, Mohamed Ist University, Oujda, Morocco
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Laboratory of Epidemiology, Clinical Research and Public Health
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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
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Calcinosis cutis is common in autoimmune connective diseases. However, to our knowledge, it has never been reported in humans with Cushing’s disease.
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Given the rarity of this association, the diagnostic approach to calcinosis cutis must exclude the other etiologies.
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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.
Department of Endocrinology, The Austin Hospital, Heidelberg, Victoria, Australia
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
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Department of Endocrinology, Monash Health, Clayton, Victoria, Australia
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Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
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Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
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Women’s Health Research Program, School of Public Health and Preventative Medicine, Monash University, Melbourne, Victoria, Australia
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Summary
Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis and prescribed antiresorptive therapy, a treatment which may increase fracture risk. Adult-onset HPPhypophosphatasia was identified in a 40-year-old woman who presented with bilateral atypical femoral fractures after 4 years of denosumab therapy. A low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level signalled the diagnosis, which was later confirmed by identification of two recessive mutations of the ALPL gene. The patient was treated with teriparatide given the unavailability of ALP enzyme-replacement therapy (asfotase alfa). Fracture healing occurred, but impaired mobility persisted. HPP predisposes to atypical femoral fracture (AFF) during antiresorptive therapy; hence, bisphosphonates and denosumab are contraindicated in this condition. Screening patients with fracture or ‘osteoporosis’ to identify a low ALP level is recommended.
Learning points
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Hypophosphatasia (HPP) is a rare and under-recognised cause of bone fragility produced by impaired matrix mineralisation that can be misdiagnosed as a fragility fracture due to age-related bone loss.
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Antiresorptive therapy is contraindicated in HPP.
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Low serum alkaline phosphatase (ALP) provides a clue to the diagnosis.
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Elevated serum vitamin B6 (an ALP substrate) is indicative of HPP, while identification of a mutation in the ALPL gene is confirmatory.
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Enzyme therapy with recombinant ALP (asfotase alfa) is currently prohibitively costly.
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Treatment with anabolic bone agents such as teriparatide has been reported, but whether normally mineralized bone is formed requires further study.
