Introduction
Hypercalcemia is a common finding in the emergency department, ranging between 0.7% to 7.5% of visits [ 1 - 4 ]. Manifestations are diverse, including gastrointestinal symptoms, muscle weakness, neuropsychiatric changes, bone pain, and fatigue.
Workup begins with evaluating for primary hyperparathyroidism, the most common cause of hypercalcemia. Nearly 80% of cases of primary hyperparathyroidism are secondary to adenoma formation in a single parathyroid gland [ 5 ]. Risk factors include head and neck radiation, as well as long-standing lithium use.
Patients with a parathyroid hormone-independent process warrant further assessment. Paraneoplastic processes are the second most common etiology of hypercalcemia [ 5 ], often developing from the secretion of parathyroid hormone-related protein (PTHrP) in squamous cell carcinoma or adenocarcinoma [ 5 , 6 ]. PTHrP promotes the synthesis of receptor activator of nuclear factor-kappa B ligand (RANKL), thereby increasing bone resorption [ 7 ]. Metastatic disease, including breast cancer, multiple myeloma, and Hodgkin and non-Hodgkin lymphoma, may precipitate hypercalcemia through a cascade of inflammatory cytokines that stimulate RANKL [ 7 ].
Other etiologies of parathyroid hormone-independent hypercalcemia include exogenous vitamin D intoxication, medication adverse effects, endocrinopathies, immobility, and, less commonly, granulomatous diseases [ 5 ].
Granulomatous disease is an infrequent finding on bone marrow biopsy, with an incidence estimated between 0.3% and 2.2% [ 8 ]. Hypercalcemia is driven by increased macrophage production of 1-alpha-hydroxylase, converting inactive vitamin D into the active form [ 5 ]. Given the broad differential for granulomatous disease, a precise diagnosis may be challenging. Here, we present a case of recurrent, symptomatic hypercalcemia from sarcoidosis isolated to the bone marrow with clinical response to glucocorticoid therapy.
Case presentation
An 84-year-old female, with a history of paroxysmal atrial fibrillation, heart failure with preserved ejection fraction, and chronic kidney disease stage IIIa, presented to the emergency department for lower extremity weakness and cramping pains resulting in recurrent falls. On further review, she reported three recent hospital visits for similar concerns with labs concerning for moderate hypercalcemia (maximum Ca2+ of 13.3 mg/dL; reference range, 8.5-10.5 mg/dL) with an appropriately suppressed parathyroid hormone (PTH) level. Workup during those visits was negative for multiple myeloma. She denied any recent history of surgery or period of immobility.
On admission, labs were remarkable for Ca2+ 15.3 mg/dL (reference range 8.5-10.5 mg/dL, Table 1 ), with ionized Ca2+ 7.1 mg/dL (reference range 4.57-5.43 mg/dL). PTH was appropriately low at 6 pg/mL (reference range 15-65 pg/mL), and PTH-related peptide was 0.8 pmol/L (reference range less than or equal to 4.2 pmol/L). 25-OH vitamin D was in the normal range at 51 ng/mL (reference range 20-80 ng/mL), while 1,25-OH vitamin D was elevated at 152 pg/mL (reference range 19.9-79.3 pg/mL). An angiotensin-converting enzyme level returned elevated at 114 u/L (reference range, 16-85 u/L). Her creatinine was elevated to 3.22 mg/dL, up from a baseline of 1.2 mg/dL. Over the preceding three months, she had developed a chronic pancytopenia with white blood cell count as low as 1.7 K/mm3 (reference range 3.7-10.5 K/mm3), hemoglobin nadir of 9.6 g/dL (reference range 11.9-15.5 g/dL), and platelet nadir of 117 K/mm3 (reference range 150-400 K/mm3).
Table 1
Comprehensive laboratory workup
| Lab Test | Result | Reference Range |
| Calcium (Ca²⁺) | 15.3 mg/dL | 8.5 – 10.5 mg/dL |
| Ionized Calcium (Ca²⁺) | 7.1 mg/dL | 4.57 – 5.43 mg/dL |
| Parathyroid Hormone (PTH) | 6 pg/mL | 15 – 65 pg/mL |
| PTH-Related Peptide (PTHrP) | 0.8 pmol/L | ≤ 4.2 pmol/L |
| 25-OH Vitamin D | 51 ng/mL | 20 – 80 ng/mL |
| 1,25-OH Vitamin D | 152 pg/mL | 19.9 – 79.3 pg/mL |
| ACE (Angiotensin-Converting Enzyme) | 114 U/L | 16 – 85 U/L |
| Creatinine | 3.22 mg/dL | 0.51 – 0.95 mg/dL |
| WBC Count | 1.7 K/MM³ | 3.7 – 10.5 K/mm³ |
| Hemoglobin | 9.6 g/dL | 11.9 – 15.5 g/dL |
| Platelet Count | 117 K/MM³ | 150 – 400 K/mm³ |
Given PTH-independent hypercalcemia with inappropriately elevated 1,25-OH vitamin D, a malignancy workup was pursued. Computed tomography of the chest/abdomen/pelvis was negative for lymphadenopathy or masses (Figure 1 ), while a skeletal survey was negative for lytic lesions (Figure 2 ). Repeat serum and urine protein electrophoresis did not demonstrate monoclonal proteins.
In the setting of chronic pancytopenia, a bone marrow biopsy was obtained to rule out a hypo-proliferative process. The bone marrow biopsy report noted multiple foci of non-necrotizing granulomas with negative fungal and mycobacterial stains, negative cytomegalovirus (CMV) staining, and negative Epstein-Barr virus (EBV) EBER (Epstein-Barr virus-encoded RNA) study, and no evidence of plasma cell neoplasm, myelodysplastic syndrome, nor histiocytic neoplasm (Figure 3 ).
Rheumatology and infectious disease services were consulted. The patient’s physical exam was unrevealing. A broad infectious workup was completed, returning negative for histoplasmosis, blastomycosis, coccidiomycosis, (1,3)-beta-D-glucan, human immunodeficiency virus, hepatitis B and hepatitis C virus, CMV, EBV, syphilis, Brucella spp., Bartonella spp., Coxiella burnetti, and Mycobacterium tuberculosis.
With an exhaustive workup demonstrating no definitive etiology of the bone marrow granulomas, our patient was started on high-dose prednisone for treatment of an atypical presentation of sarcoidosis isolated to the bone marrow. She was discharged home after an interval improvement in serum calcium and symptoms. On follow-up several weeks later in the rheumatology clinic, she had sustained resolution of hypercalcemia and was started on leflunomide as a steroid-sparing agent (Figure 4 ). Importantly, the patient tolerated the slow taper of prednisone without any recurrence of symptoms, with monitoring labs remaining stable on follow-up several months later.
Discussion
The differential diagnosis for granulomatous bone marrow disease is quite broad, including malignancy, infection, drug-associated, connective tissue disease, and sarcoidosis.
Malignant neoplasms are commonly identified as the precipitating event of bone marrow granulomas [ 8 ]. While Hodgkin and non-Hodgkin lymphomas are frequently noted, non-hematologic malignancies, such as ovarian, urothelial, and colonic carcinomas, are also described [ 8 , 9 ]. Infectious etiologies include tuberculous and nontuberculous mycobacteria, brucellosis, disseminated fungal infections, EBV, and CMV. Drug-associated granulomas are far less common, with amiodarone, procainamide, and sulfonamides serving as culprits [ 8 , 9 ]. Ultimately, as many as 13% of cases of bone marrow granulomas remain without a known cause [ 8 ]. The long-term prognosis is often favorable in those patients [ 9 ].
Infiltration of the bone marrow is a rare feature of sarcoidosis [ 10 , 11 ]. Classic illness scripts depict a younger female patient with respiratory symptoms and imaging findings of bilateral hilar adenopathy [ 12 ]. Nearly half the patients have extra-pulmonary manifestations, the earliest of which include vision changes, rash, and inflammatory arthritis. However, these findings may also be absent, as seen here.
Hypercalcemia in granulomatous diseases like sarcoidosis is mediated through increased macrophage activity of 1-alpha-hydroxylase. Notably, glucocorticoids suppress the activity of 1-alpha-hydroxylase, rapidly correcting hypercalcemia [ 13 ]. Glucocorticoids remain the first-line agent for treatment of pulmonary sarcoidosis and extrapulmonary disease, including bone sarcoidosis, given the evidence for prevention of disease progression and improvement of quality of life [ 14 - 16 ]. Cases of steroid-refractory hypercalcemia have been reported, with patients often responding to ketoconazole (a potent inhibitor of 1-alpha-hydroxylase and other cytochrome P450 enzymes) [ 17 , 18 ].
Given concerns for significant adverse effects from prolonged steroid therapy (such as osteoporosis in an elderly female), consideration is often given for the initiation of steroid-sparing agents. Antimetabolites like methotrexate, azathioprine, or leflunomide are second-line therapies, with anti-tumor necrosis factor agents like infliximab serving as third-line [ 14 , 18 , 19 ]. Here, methotrexate was not favored due to its toxicity profile and the patient’s renal injury, while the risk for azathioprine-related arthralgias and vision changes contributing to falls was considered. In a small study, leflunomide was found to be effective in the treatment of patients with sarcoidosis intolerant to methotrexate, and in another study, 83% of patients with extrapulmonary disease had a partial or good response to therapy [ 20 , 21 ]. After carefully weighing the adverse effects against the above context, leflunomide was ultimately selected as our patient’s steroid-sparing agent.
Conclusions
In cases of hypercalcemia where initial workup is unrevealing for primary hyperparathyroidism or malignancy, clinicians should maintain a high index of suspicion for granulomatous diseases. Here, we highlight an exceedingly rare case of isolated bone marrow granulomas and the importance of keeping a broad differential. Ruling out other etiologies of granulomatous bone marrow diseases was imperative to narrowing our patient’s differential diagnosis to sarcoidosis and initiating timely therapy. Glucocorticoids remain the first-line therapy for sarcoidosis, effectively lowering calcium levels by suppressing inflammation and vitamin D synthesis.
Disclosures
Human subjects: Informed consent for treatment and open access publication was obtained or waived by all participants in this study.
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:
Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.
Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.
Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
Author Contributions
Concept and design: Alp S. Kahveci, Brittany Bettendorf, Lindsay Moy
Drafting of the manuscript: Alp S. Kahveci, Brittany Bettendorf, Lindsay Moy, Mohamed M. Eletrebi
Critical review of the manuscript for important intellectual content: Alp S. Kahveci, Brittany Bettendorf, Lindsay Moy
Supervision: Brittany Bettendorf
Acquisition, analysis, or interpretation of data: Mohamed M. Eletrebi
References
1 Hypercalcemia in the emergency department Am J Med Sci Lee CT Yang CC Lam KK Kung CT Tsai CJ Chen HC 119 123 331 2006 16538071 10.1097/00000441-200603000-00002
2 Hypercalcemia in the ED: prevalence, etiology, and outcome Am J Emerg Med Lindner G Felber R Schwarz C 657 660 31 2013 23246111 10.1016/j.ajem.2012.11.010
3 Calcium disorders in the emergency department: independent risk factors for mortality PLoS One Sauter TC Lindner G Ahmad SS Leichtle AB Fiedler GM Exadaktylos AK Haider DG 0 10 2015 10.1371/journal.pone.0132788 PMC4501826 26172117
4 Characteristics and outcome of severe hypercalcemia on admission to the emergency department: a retrospective cohort study Swiss Med Wkly Ravioli S Lafranchi A Exadaktylos AK Haidinger M Lindner G 40069 153 2023 37191138 10.57187/smw.2023.40069
5 A review of current clinical concepts in the pathophysiology, etiology, diagnosis, and management of hypercalcemia Med Sci Monit Tonon CR Silva TA Pereira FW 0 28 2022 10.12659/MSM.935821 PMC8889795 35217631
6 PTHrP-mediated hypercalcemia: causes and survival in 138 patients J Clin Endocrinol Metab Donovan PJ Achong N Griffin K Galligan J Pretorius CJ McLeod DS 2024 2029 100 2015 25719931 10.1210/jc.2014-4250
7 Cancer-related hypercalcemia J Oncol Pract Goldner W 426 432 12 2016 27170690 10.1200/JOP.2016.011155
8 Differential diagnoses of bone marrow granuloma West J Med Eid A Carion W Nystrom JS 510 515 164 1996 https://pmc.ncbi.nlm.nih.gov/articles/PMC1303627/ 8764626 PMC1303627
9 Granulomatous lesions in bone marrow: clinicopathologic findings and significance in a study of 48 cases Eur J Intern Med Brackers de Hugo L Ffrench M Broussolle C Sève P 468 473 24 2013 23414770 10.1016/j.ejim.2012.11.008
10 Bone and joint sarcoidosis Semin Arthritis Rheum James DG Neville E Carstairs LS 53 81 6 1976 785605 10.1016/s0049-0172(76)80005-4
11 Sarcoidal anemia and leukopenia treated with methotrexate and mycophenolate mofetil Arch Dermatol Kalajian AH Van Meter JR Callen JP 905 909 145 2009 19687421 10.1001/archdermatol.2009.75
12 Sarcoidosis: a clinical overview from symptoms to diagnosis Cells Sève P Pacheco Y Durupt F 766 10 2021 33807303 10.3390/cells10040766 PMC8066110
13 Hypercalcemia as a result of sarcoidosis with normal serum concentrations of vitamin D Med Sci Monit Falk S Kratzsch J Paschke R Koch CA 133 136 13 2007 https://medscimonit.com/abstract/index/idArt/512936 17968303
14 A comprehensive review of sarcoidosis treatment for pulmonologists Pulm Ther Melani AS Bigliazzi C Cimmino FA Bergantini L Bargagli E 325 344 7 2021 34143362 10.1007/s41030-021-00160-x PMC8589889
15 State-of-the-art treatments for sarcoidosis Methodist Debakey Cardiovasc J Papanikolaou IC Antonakis E Pandi A 94 105 18 2022 10.14797/mdcvj.1068 PMC9237819 35772032
16 Clinical characteristics of patients with bone sarcoidosis Semin Arthritis Rheum Zhou Y Lower EE Li H Farhey Y Baughman RP 143 148 47 2017 28274482 10.1016/j.semarthrit.2017.02.004
17 Treatment of sarcoidosis-associated hypercalcemia with ketoconazole Am J Kidney Dis Bia MJ Insogna K 702 705 18 1991 1962657 10.1016/s0272-6386(12)80613-5
18 Diagnostic challenges in a case of refractory severe hypercalcemia due to splenic sarcoidosis JCEM Case Rep Knott JA Horvath AR Htet TD 0 3 2025 10.1210/jcemcr/luaf011 PMC11791341 39906901
19 Use of methotrexate in patients with sarcoidosis Clin Exp Rheumatol Kiltz U Braun J 183 185 28 2010 https://www.clinexprheumatol.org/abstract.asp?a=4175 21044457
20 Leflunomide for chronic sarcoidosis Sarcoidosis Vasc Diffuse Lung Dis Baughman RP Lower EE 43 48 21 2004 15127974 10.1007/s11083-004-5178-y
21 Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis Eur Respir J Sahoo DH Bandyopadhyay D Xu M 1145 1150 38 2011 21565914 10.1183/09031936.00195010