The Impact of Metastatic Bone Cancers on Serum Calcium Levels: A Focused Analysis of Patient Outcomes

By Muhammad Khizar Memon¹, Syed Uzair Mahmood², Sidra Memon³, Azhar Rashid⁴, Muhammad Ali Memon⁵, Shahzad Ali Jiskani⁶

Doi: https://doi.org/10.36283/ziun-pjmd14-1/002

How to cite: Memon MK, Mahmood SU, Memon S, Rashid A, Memon MA, Jiskani SA The Impact of Metastatic Bone Cancers on Serum Calcium Levels: A Focused Analysis of Patient Outcomes. Pak J Med Dent. 2025 Jan;14(1): 3-9. Doi: https://doi.org/10.36283/ziun-pjmd14-1/002

Received: Mon, October 21, 2024 Accepted: Tue, December 10, 2024 Published: Fri, January 10, 2025

Background: Metastatic bone cancers are a significant clinical problem because metastasis disrupts normal bone homeostasis, including calcium dysregulation. Much less is known about hypocalcemia and its clinical consequences. The study analyzed serum calcium changes in metastatic bone cancer patients, assessed differences across diagnoses and clinical stages, and evaluated alkaline phosphatase levels and types of bone lesions.

Methods: A prospective study was conducted on 100 metastatic bone cancers using convenience sampling, at Indus Medical College Hospital, between March and April 2020. The patients were categorized based on the principle tumor type, clinical stage, and bone scan results. Serum calcium, corrected calcium, albumin, and ALP are measured and analyzed using descriptive and inferential statistics. Data analysis was done by SPSS using one-way ANOVA, t-tests, Pearson correlation, regression analysis, and Chi-square tests. A p-value of <0.05 was considered significant.

Results: The mean serum calcium was 8.5 ± 0.6 mg/dl. The corrected calcium level of the patients with breast cancer was statistically lower compared with the prostate cancer patients – 8.3 ± 0.5 mg/dl (p = 0.01) compared with 9.0 ± 0.6 mg/dl. The levels of ALP in blastic lesions were higher than in lytic ones, amounting to 600 ± 300 IU/L and 250 ± 100 IU/L, respectively. There was marked regression in the main diagnosis and ALP levels, which occurred with serum calcium being altered in breast cancer.

Conclusion: Serum calcium levels vary significantly among different types of cancers and stages, suggesting a vigilant monitoring of calcium and ALP levels in clinical practice.

Keywords: Metastatic Bone Cancer, Serum Calcium, Alkaline Phosphatase, Calcium Dysregulation, Hypocalcemia

Metastatic bone cancers represent a significant clinical challenge, particularly in their ability to disrupt normal bone homeostasis. Bone is a common site for metastasis, particularly from primary tumors of the breast, prostate, lung, and kidney^1,2. The process of bone metastasis involves the complex interaction of tumor cells with the bone microenvironment, leading to either osteolytic or osteoblastic lesions, depending on the type of cancer and its biological behavior. These interactions frequently result in the dysregulation of bone remodeling processes, leading to abnormal serum calcium levels – a condition with significant clinical implications³.

Calcium homeostasis is tightly regulated by the coordinated actions of the parathyroid hormone (PTH), calcitonin, and vitamin D, which act on the bones, kidneys, and gastrointestinal tract to maintain serum calcium levels with a narrow physiological range^4,5. In the context of bone metastasis, however, this regulation can become profoundly disturbed. Tumor-induced bone resorption, driven by osteoclast activation, is a major cause of hypercalcemia in patients with metastatic bone disease. The release of calcium from the bone into the bloodstream not only leads to hypercalcemia but also contributes to a range of symptoms including nausea, vomiting, fatigue, and confusion, and in severe cases, can lead to renal failure and cardiac arrhythmias^6,7,8.

Conversely, certain metastatic cancers can induce hypocalcemia, though this is less common^{9,10,11,12,13}. Hypocalcemia in the context of cancer may result from several mechanisms, including the consumption of calcium by rapidly growing tumor cells, or impaired calcium mobilization due to extensive osteoblastic activity, particularly in prostate cancer metastases¹⁴. The prevalence and severity of calcium dysregulation in metastatic bone cancer are underexplored, especially compared to primary bone cancers. Current literature reveals a gap in studies examining serum changes across different bone malignancies. While hypercalcemia is more common in metastatic disease, the mechanisms behind these differences are not fully understood, and clinical management remains challenging, with treatments offering only temporary relief. This study aimed to explore the changes in serum calcium levels in patients with metastatic bone cancers, providing a comparative analysis with patients suffering from primary bone cancers and a healthy control group. By examining these differences, we seek to enhance the understanding of the pathophysiological mechanisms underlying serum alterations in metastatic bone disease and to inform clinical practice in the management of these patients. The findings could have significant implications for the clinical management of patients, potentially leading to improved prognostic tools and more effective therapeutic strategies. In addition to filling a critical gap in the literature, this study challenges the prevailing assumptions about the uniformity of calcium homeostasis in bone-related malignancies.

This was a prospective study conducted on patients diagnosed with metastatic bone cancers (No. IMC/ERB/2020-13). Data was collected at Indus Medical College Hospital, from March 2020 to April 2020. All 100 patients included using convenience sampling in the study had confirmed bone metastasis secondary to various cancers. The sample size was calculated using the WHO sample size calculator with 95% confidence and 5% margin of error. The study includes patients with confirmed bone metastases through clinical diagnosis and imaging (bone scans). Serum calcium and albumin levels were documented. Patients with incomplete data or unconfirmed diagnoses were excluded. Clinical and laboratory variables were assessed, alongside cancer stages categorized as localized, advanced, or metastatic.

Data analysis involved descriptive and inferential statistics. Continuous variables were summarized as mean ± SD and categorical variables as frequencies. Comparative analysis using one-way ANOVA for serum calcium across cancer types, t-tests for calcium differences and lesion types, and Pearson correlation for the relationship between calcium levels. Regression analysis identified predictors of calcium levels, including cancer types and ALP. Chi-square tests assessed hypo- and hypercalcemia rates across cancer types and stages. A p-value of <0.05 was considered statistically significant.

Table 1: Demographic and Clinical Parameters of Patients (n=100)

The study took part with a total of 100 patients diagnosed with metastatic bone cancers. The mean age of the patients was 58 ± 12 years, ranging from 14 to 85 years Table 1.

Table 2: Frequency Distribution of Primary Tumor Diagnosis (n=100)

The most common primary cancers were found to be breast cancer 49%, followed by 11% lung, 9% prostate, etc. Table 2.

The mean serum calcium level was at 8.5 ± 0.6 mg/dl, and 15% of the patients were classified as hypocalcemia, while 10% were hypercalcemic. The lowest average calcium levels were found in breast cancer patients at 8.3 ± 0.5 mg/dl, while prostate cancer patients had the highest average of 9.0 ± 0.6 mg/dl. The mean corrected values for calcium levels were 8.6 ± 0.7 mg/dl. The overall prevalence of hypocalcemia was reduced after hypoalbuminemia had been corrected. A total of 10% of the patients still received the diagnosis of hypocalcemia. The corrected levels of calcium were compared between breast and prostate cancer patients to show that they were significantly lower in patients with breast cancer than in those with prostate cancer, with a value of p < 0.05.

 Table 3: Comparison of Serum Alkaline Phosphatase and Corrected Calcium Levels with Type of Lesion (n=100)

The mean alkaline phosphatase level was 400 ± 300 IU/L. ALP levels were higher in blastic lesions compared with lytic lesions (mean: 600 IU/L for blastic and 250 IU/L for lytic) Table 3.

Table 4: Relationship between Clinical Stage and Corrected Calcium Levels (n=100)

Statistical analysis for serum calcium found the differences to be significant among primary diagnoses, p=0.03. The calcium levels differed at very significant levels among blastic, lytic, and mixed bone lesions as estimated by p = 0.02; the blastic lesions showed a significantly higher level of serum calcium. The relationship of the clinical stage with corrected calcium levels is summarized in Table 4.

Table 5: Post-hoc Analysis for Clinical Stages of Tumors (n=100)

Table 5 illustrates the corrected calcium levels across different clinical stages. A significant difference was observed between groups by post-hoc analysis.

Table 6: Linear Regression Analysis of Serum Calcium Levels (n=100)

Linear regression analysis showed that the main diagnosis and alkaline phosphatase levels were significant independent predictors of serum calcium levels, with breast cancer patients being more likely to have lower levels of calcium levels, and the higher the ALP levels, the lower the level of serum calcium Table 6.

Gender analysis shows female predominance (55%) as compared to males (45%) (Figure 1).

Figure 1: Gender Analysis of Patients (n=100)

The study highlights multifaceted changes in serum calcium levels among metastatic bone cancer patients, reflecting significant calcium homeostasis imbalances. Both hypercalcemia and hypocalcemia were observed, consistent with previous studies. Up to 30% of patients with bone metastasis experience hypercalcemia, often linked to osteolytic activity in cancers. On the contrary, Rizzo et al. mentioned that hypocalcemia is very frequent in patients with disseminated osteoblastic lesions, such as prostate cancer¹⁵. Our findings showed that breast cancer patients had significantly lower serum calcium levels, with corrected calcium values markedly reduced compared to prostate cancer patients. This aligns with Darawshi et al. highlighting profound hypocalcemia in breast cancer due to increased osteoclastic activity linked to disease activity¹⁵. This highlights the need for careful monitoring of calcium levels in breast cancer patients, particularly as treatment changes can significantly impact metabolic dynamics.

The study found significantly higher ALP levels in blastic lesions compared to lytic lesions, reinforcing bone scans and greater metastatic involvement, emphasizing the need for clinical assessment of these biomarkers. Additionally, corrected calcium levels decreased in early metastatic states, aligning with Biodini et al.’s findings that increasing metastatic burden disrupts metabolic homeostasis¹⁶. By advancing cancer progression, patients may experience bone turnover and abnormality of calcium metabolism hence need the ability to adaptively manage these areas to proactively influence changes^17,18,19,20. Linear regression analysis identified predictors of serum calcium levels, including primary diagnosis and ALP levels. A negative coefficient for breast cancer diagnosis and ALP suggests that breast cancer patients with higher ALP levels are more likely to have lower serum calcium, consistent with Generali et al.’s finding on bone metabolism changes in metastatic disease²¹.

This highlights the importance of monitoring serum calcium and ALP in patients with metastatic bone cancer, particularly with the emergence of new therapies affecting bone remodeling. This study has several limitations, including single-center data sources, and a limited sample size that may not represent all cancer types or demographics. Key variables, such as renal function, dietary calcium intake, and medications, were not included but could impact calcium levels. Future studies should involve larger, multi-center cohorts and longitudinal designs to better validate results and understand serum calcium changes over time. Additionally, molecular insights into calcium dysregulation in cancer may lead to targeted therapies. Understanding patient profiles and treatment interactions with calcium metabolism is crucial for the personalized management of calcium dysregulation in metastatic bone disease.

These findings highlight a gap in understanding calcium homeostasis in metastatic bone diseases. While hypercalcemia is well-studied, the clinical implications of hypocalcemia, particularly in prostate cancer, are less explored. These patients face the added challenge of low serum calcium levels and treatment-related bone complications^22,23,24,25. The complexity of tumor biology and its interaction with the bone microenvironment requires incorporating bone health into treatment plans. Understanding the relationship between tumor biology, treatments, and metabolic effects, particularly calcium metabolism, is essential for developing personalized approaches and improving patient prognosis.

The study highlighted significant serum calcium dysregulation in metastatic bone cancers, with breast cancer patients exhibiting lower calcium levels due to osteoclastic activity. Elevated alkaline phosphatase levels in blastic lesions underscore its role as a marker of bone turnover. The progressive calcium decline from early to metastatic stage emphasizes the need for dynamic monitoring and tailored interventions. Further research on hypocalcemia is essential to enhance personalized management and improve patient outcomes.

ALP: alkaline phosphatase

PTH: parathyroid hormone

SD: standard deviation

WHO: World Health Organization

The authors acknowledge the institution for their immense support.

The authors declare no conflict of interest.

The authors did not receive any funding.

The ethical approval was obtained from the ethical review board of the institution (No. IMC/ERB/2020-13).

MKM Conceptualization, data analysis, methodology, SUM Data analysis, methodology, editing the manuscript, SD Review of manuscript, data analysis, AZ Supervision, critical review, editing the manuscript, MAM Data collection, statistical analysis, SAJ manuscript writing, data interpretation, methodology.

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