Introduction

Hip fracture is one of the most commonly faced conditions by Orthopaedic surgeons in Hong Kong, with the majority of patients belonging to the geriatric population with high risk of osteoporosis. (1) Osteoporosis is a condition characterized by decrease in bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. Common sites at risk are the hips, vertebrae and distal forearm. While it may present as height loss due to vertebral collapse, it is commonly asymptomatic and unknown to patients until they suffer from fractures. It is therefore reasonable to have a high suspicion when a patient presents with fractures at the above regions, particularly those resulting from a low-energy injury (2)(3). Some studies have shown that up to 30% of post-menopausal women and 50 to 80% of men are found to have factors contributing to osteoporosis when undergoing an evaluation for underlying causes of the disease (4)(5)(6), common examples are vitamin D deficiency, hyperthyroidism, hyperparathyroidism, diabetes mellitus, multiple myeloma and secondary to use of corticosteroids (6)(7).

Hyperthyroidism accelerates bone turnover processes, leading to increased bone resorption which surpasses formation, thus enhancing fracture susceptibility. Similarly, hyperparathyroidism, predominantly through excess parathyroid hormone (PTH) activity, promotes excessive calcium mobilization from bone stores into the bloodstream, consequently weakening skeletal integrity. Meanwhile, multiple myeloma, characterized by malignant proliferation of plasma cells in bone marrow, not only disrupts normal bone remodelling but also induces osteolysis that further compromise bone density. The characteristic C.R.A.B. symptoms of multiple myeloma refer to hypercalcemia, renal impairment, anemia and lytic bone lesions. (8) Studies have also shown increase in erythrocyte sedimentation rate (ESR) and reversed albumin-globulin (A/G) ratio as an indicator of multiple myeloma. (9)(10)

According to the Osteoporosis Society of Hong Kong Guidelines, to work up for secondary causes of osteoporosis, basic laboratory investigations should include complete blood count, erythrocyte sedimentation rate, liver and renal function tests (including alkaline phosphatase, serum calcium and phosphate), thyroid function, and a 24-hour urine test for calcium excretion. Testosterone level should be considered in men. Additional special tests such as serum protein electrophoresis, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD) and cortisol level may be considered if the history and initial workup suggest a related disorder. Specific bone marker tests may be considered, if available (3).

In this study we aim to investigate the prevalence of secondary osteoporosis with hip fracture as first presentation, and whether the current screening protocols adopted are effective in identifying secondary causes of osteoporosis in a regional hospital. We specifically focus on hyperthyroidism, hyperparathyroidism and multiple myeloma in this study due to their relevance to the above investigations.

Study design

This research implements a retrospective study design conducted at a regional hospital in Hong Kong, focusing on patients admitted with hip fractures. The objective was to assess the prevalence and underlying causes of secondary osteoporosis, specifically hyperthyroidism, hyperparathyroidism, and multiple myeloma among this patient population.

Patient selection

This study included patients admitted to a regional hospital in Hong Kong for hip fractures with operation done from January 2020 to December 2021. Patient information for those who have received surgery was retrieved from the hospital’s operative record database using ICD codes specific to hip fractures. Patients receiving revision surgery or already have suffered from previous hip fractures, those known to have secondary osteoporosis and cases that suffered from pathological fracture are excluded from this study.

Data collection

All patients who were admitted for hip fractures routinely underwent investigations according to the Osteoporosis Society of Hong Kong Guidelines. Data were extracted from the electronic patient record system, focusing on demographic information, medical history, and laboratory results captured upon admission. Key blood tests reviewed included complete blood counts, alkaline phosphatase (ALP), estimated glomerular filtration rate (eGFR), serum calcium, thyroid-stimulating hormone (TSH), and erythrocyte sedimentation rate (ESR).

Each case meeting the criteria for potential secondary osteoporosis was thoroughly reviewed in conjunction with patient histories and clinical assessments to confirm the diagnosis. Elevated calcium levels were analysed for potential hyperparathyroidism, while suppressed TSH levels were indicative of hyperthyroid states. The presence of significantly elevated ESR levels and reversed albumin-globulin ratio prompted further examination for multiple myeloma. A measurement of 40mm/hr was used as cutoff for ESR levels. This is in accordance with previous studies and will increase the specificity of the test. Additional data on serum and urine protein electrophoresis and urine Bence Jones protein were evaluated to identify potential cases of multiple myeloma. Thyroxine levels and parathyroid hormone levels were measured to identify the presence of hyperthyroidism and hyperparathyroidism respectively. The C.R.A.B. symptoms of multiple myeloma are somewhat nonspecific and is unlikely to provide any value in the screening of multiple myeloma.

Statistical Analysis

Descriptive statistics were used to summarize general patient demographics and laboratory findings. Prevalence rates of secondary osteoporosis causes including hyperthyroidism, hyperparathyroidism, and multiple myeloma, were calculated. Comparative analyses using chi-square and t-tests were conducted where appropriate to explore associations of different blood parameters between different screening cohorts. P-value less than 0.05 was considered to be statistically significant.

Results

Patient demographics - 1216 patients received hip fracture surgery at the hospital from January 2020 to December 2021. 95 cases were excluded from this study according to the above-mentioned criteria. There were 322 male and 799 female. Male to female ratio was 3:7. The mean age was 85 years old (range 65 to 103).

Hyperthyroidism – Out of the cohort, 51 subjects (4.5%) exhibited low TSH levels. Further testing of thyroxine levels (fT4) confirmed that 4 patients (0.4%) have hyperthyroidism. The remaining 47 patients are categorized as having subclinical hyperthyroidism. The mean age of patients who had screened positive was 84.4 years (SD=7.6, n=51), which is slightly younger than those who had screened negative, 84.7 years (SD=8.1, n=1070) (Table 1). However, independent t-test revealed no statistically significant difference in mean age between the two groups. Chi-square test revealed that there is no statistically significant association of patients’ sex and screening positive for hyperthyroidism (p = 0.60). These indicates that age and sex does not influence the likelihood of screening positive for hyperthyroidism.

Hyperparathyroidism - Hypercalcemia was tested as screening parameter for hyperparathyroidism. Among the study population, hypercalcemia was present in 6 patients (0.5%). Further testing of serum parathyroid hormone levels led to the diagnosis of hyperparathyroidism in 4 patients (0.4%). The mean age of patients who had screened positive was slightly older. (Table 1) We have noticed no statistically significant difference in mean age between the two groups. Chi-square test revealed that there is no statistically significant association of patients’ sex and screening positive for hyperthyroidism (p = 0.51).

Multiple myeloma - We have not identified any patients with multiple myeloma in this study. Despite the presence of reversed albumin-globulin (A/G) ratio in 310 (27.7%) subjects and elevated ESR in 271 (35.9%) patients, serum protein electrophoresis and urine Bence Jones protein were all negative for abnormal monoclonal bands. An increase in age, however, was found to be associated with presence of reversed A/G ratio and elevated ESR. 

Table 1

Discussion

Geriatric hip fracture has profound impact on the population with osteoporosis being a major risk factor. It’s management requires a multidisciplinary approach, led by Orthopaedic surgeons and Geriatricians. This study reveals critical insights into the relationship between hip fractures and potential secondary causes of osteoporosis, focusing specifically on hyperthyroidism, hyperthyroidism and multiple myeloma. Our findings underscore the complexity of diagnosing secondary osteoporosis in geriatric patients presenting with hip fractures.

Population studies conducted in Hong Kong and Europe has found that the incidence of hyperthyroidism to be 0.75% (11), and that of primary hyperparathyroidism was 0.3% in the general population.(12) The prevalence demonstrated in this study, 0.4% and 0.4% respectively, was comparable to the prevalence in the overall population. Hyperthyroidism, identified in 0.4% of patients, plays its role as a possible but infrequent secondary cause of osteoporosis leading to hip fractures. The presence of subclinical hyperthyroidism in 4.5% of patients suggests a potential sub-threshold hormonal influence on bone density that warrants further clinical attention and follow-up. Similarly, hyperparathyroidism exhibited in 0.4% of the population also aligns with existing prevalence figures. These findings highlight the need for adherence to vigilant screening, as hyperparathyroidism's metabolic effects, such as elevated calcium and altered phosphorous balance, can significantly impact bone resorption rates.

On the contrary, despite over 1000 subjects included in this study, we found no cases of multiple myeloma. While C.R.A.B. symptoms and reversed albumin-globulin ratio were prevalent, their lack of specificity suggests that routine indicators like anaemia and renal impairment, influenced by aging and nutritional status, overshadowed potential myeloma-specific presentations. This underscores the necessity for more sensitive and specific diagnostic approaches in screening for multiple myeloma in the elderly. Further data is required to demonstrate the significance of screening tests for multiple myeloma.

An unexpected discovery was the high rate of subclinical abnormalities, particularly concerning the albumin-globulin ratio, which correlated with age-related changes. This requires further attention to differentiate between changes due to aging and those indicating underlying disease processes.

The retrospective nature of this study and potential incomplete adherence to the screening process limited our ability to generalize findings. Future studies should focus on larger, prospectively designed cohorts and refine screening methodologies, particularly for conditions like multiple myeloma. Moreover, many other secondary causes of osteoporosis have not been addressed in this study. More effort should be put in to look for include such conditions to further substantiate the value of screening tests for each condition.

Conclusion

In this study, we were able to identify patients with hyperthyroidism and primary hyperparathyroidism among those presenting with hip fractures with the current screening tests. However, no cases of multiple myeloma were detected in this study. Patients with older age are more likely to present with reverse A/G ratio, anemia and renal impairment. While our study supports the inclusion of hyperthyroidism and hyperparathyroidism in the differential diagnosis for secondary osteoporosis in hip fracture patients, it emphasizes the need for comprehensive and tailored screening strategies to distinguish these conditions amidst overlapping symptomatology of multiple myeloma in elderly populations.