Comparative study of 99Tc-MDP and zoledronic acid in the treatment of osteoporosis

Ying Zhou, Wei-Min Pan✉, Wen Sun, Chao-Qun Wang, Juan-Juan Yan, Quan Xie, Ying Huang, Huan Xiao, Wei-Wen Yan

1.Department Of Nuclear Medicine, The First Affiliated Hospital of Hainan Medical University, Haikou 570102,China 2.Department Of Nuclear Medicine, Hainan General Hospital, Haikou 570102,China

Keywords:Zoledronic acid Tc-MDP Osteoporosis Erythrocyte sedimentation rate Bone density

ABSTRACT Objective: To compare the efficacy and mechanism of zoledronic acid and Tc-MDP in the treatment of osteoporosis. Methods: From July 2011 to November 2015, 232 patients with primary osteoporosis were selected and treated in The First Affiliated Hospital of Hainan Medical College were selected and were divided into the 116 patients in the Tc-MDP group and 116 patients in the zoledronic acid group accorded to the treatment ways. The zoledronic acid group were given zoledronic acid treatment, 1 time in one year. The Tc-MDP group were given Tc-MDP treatment, and the treatment were treated for 10 days for 1 course, 1 course for 3 months, and a total of 3 years of treatment were observed. The prognosis and the changes of bone mineral density and hematological parameters were recorded. Results: The total effective rates of the zoledronic acid group and Tc-MDP group were 99.1% and 90.0%, respectively, and the zoledronic acid group were significantly higher than the Tc-MDP group (P＜0.05). The bone mineral density of lumbar vertebrae and hip after treatment were significantly higher than that of the two groups before treatment, and the zoledronic acid group were also significantly higher than the Tc-MDP group(P＜0.05). The joint tenderness scores of the two groups were significantly lower than those before treatment, and the Tc-MDP group were also significantly lower than the zoledronic acid group (P＜0.05). There were no significant differences in serum calcium and blood phosphorus levels compared between the two groups (P＞0.05), and the erythroeyte sedimentation rate (ESR) levels were lower than before treatment (P＜0.05), The ESR levels of the Tc-MDP group were also significantly lower than that of the zoledronic acid group (P＜0.05). Conclusion: The zoledronic acid and the application of Tc-MDP in the treatment of osteoporosis can increase bone density, relieve joint tenderness symptoms, reduce ESR content, and will not affect patients' blood calcium and blood phosphorus levels. However, zoledronic acid increases bone density significantly are better than the Yunke, and Yunke relieves joint pain significantly are more than zoledronic acid.

1. Introduction

Osteoporosis (OP) is a metabolic disorder of bone disease in which bone tissue structure is destroyed, bone organic matter and bone mineral content are reduced, trabecular bone strength is reduced, and cortical bone is thinned, which may easily lead to fracture [1-2]. With the increased of the elderly population in China and the advancement of menopausal women’ age, the number of people with Osteoporosis in China had increased year by year, directly threatened the health and quality of life of the elderly [3]. Most of the patients have no obvious impaired signs and symptoms, however, minor trauma or slight carelessness in daily life may lead to fracture[4 -5]. The disease manifests in imaging that the affected bones will show uniformity or reduced spot-like density, and the number of trabecular bones will be reduced or slim [6]. The current drugs for treating osteoporosis mainly include active vitamin D, bisphosphonates, calcitonins, calcium agents, etc. Zoledronic acid is the latest generation of bisphosphonate drugs, which can inhibit osteoclast Cell activity, increase bone density, and inhibit bone resorption [7]; However, Zoledronic has a certain effect on the shaping of neonatal epiphysis, which can increase incidence of atypical fractures and stress fractures [8-9]. Yunke (99Tc-MDP) is a complex of methylene bisphosphonate and thallium element reduced by stannous chloride, with fast blood clearance, rapid bone uptake and long-lasting effect [10-11]; it can also effectively remove free radicals and immune complexes in the body, inhibit bone resorption, enhance osteoblast activity, regulate the body's immune function, inhibit osteoclast activity, and promote new bone formation [12-13]. This article specifically compares the efficacy and mechanism of zoledronic acid and Yunke in the treatment of osteoporosis in order to clarify the therapeutic effect after using the two drugs. The summary report is as follows.

2. Materials and methods

2.1 Research Object

From July 2011 to November 2015, 232 cases of patients with primary osteoporosis who were selected to be treated in the First Affiliated Hospital of Hainan Medical College were selected, Inclusion criteria: met the diagnostic criteria for osteoporosis (bone mineral density, (BMD) ≤ 2.5 standard deviations of peak value); age 40-70 years; approved by relevant departments; patients signed informed consent; gender were not restricted; clinical datawere complete. Exclusion criteria: cases with severe cardiovascular, cerebrovascular, liver, kidney disease and mental disorders; pregnant or lactating women; cases with mental disorders; allergies; cases were took other drugs that affect bone metabolism in the past 3 months; cases lack clinical data; cases had obvious disturbance of consciousness, mental retardation or unable to communicate normally; patients with secondary osteoporosis.

All the cases were divided into the 116 patients in the Tc-MDP group and 116 patients in the zoledronic acid group accorded to the treatment ways, There were no significant difference in the course of disease, age, Kellgren-Lawrence classification, course of disease, body mass index, and so on compared between the two groups(P＜0.05). Table 1.

2.2 Treatment ways

Zoledronic acid group: Treated by the Zoledronic acidt, intravenous infusion of zoledronic acid (Microdad, Novartis Co., Ltd.) 100ml: 5mg, 30-60min / times, 1 time / 1 year for 3 consecutive years.

Tc-MDP group: Treated by the Tc-MDP (Yunke, Chengdu Yunke Pharmaceutical Co., Ltd.) A agent 5 ml (internal Contains 99Tc 0.05µg) Inject 5.5 mg of B agent (0.5 mg of stannous chloride, 5 mg of methylene diphosphonic acid) into lyophilized bottle, shake it thoroughly, let it stand for 5 minutes, intravenously, 10 mg / d, 10 d/course t, one course every 3 months. Both groups were treated for 3 years.

2.3 Observation indicators

(1) Before and after treatment, the dual-energy X-ray bone densitometer were used to detect the bone density of the lumbar spine and hip of the patients, The average of three measurements were collected. (2) Curative effect standard: marked effective: BMD change rate increased by ≧ 2.5%, pain were relieved, joints were able to move freely; effective: BMD change rate did not change or increased by ＜2.5%, pain were reduced, joint activity were acceptable; Ineffective: Not meeting the above criteria or worsening. Total effective rate = effective rate + significant efficiency. (3) All patients were detected for blood calcium and blood phosphorus content before and after treatment, and erythroeyte sedimentation rate (ESR) were also measured. (4) Twenty-eight joints in 14 joint areas before and after treatment were scored, and 3 points, 2 points, 1 point, and 0 points were recorded accorded to the levels of severe, medium, light, and none.

2.4 Statistical methods

The software used in the data research and analysis process is SPSS20.00. The data wer entered into the database through Excel. The number of cases and percentages were used to represent the count data. The mean ± standard deviation were used to representthe measurement of normality distribution Data and count data were compared using chi-square chi-square analysis, analysis of variance, and t-test to compare measurement data. The test level were α= 0.05.

Table 1:Comparison of general information between the two groups

Table2:Total efficiency comparison in the two groups(n)

Table 3: Comparison of bone mineral density before and after treatment in the two groups(g/cm3,±s)

Table 3: Comparison of bone mineral density before and after treatment in the two groups(g/cm3,±s)

groups n Lumbar spine Before treatment After treatment t P Hip Before treatment After treatment t P Tc-MDP group 116 0.67±0.09 0.74±0.08 7.022 0.009 0.65±0.11 0.73±0.15 6.552 0.012 zoledronic acid group 116 0.68±0.12 0.79±0.14 13.953 0.000 0.66±0.10 0.78±0.14 11.742 0.000 t 0.122 6.403 0.142 5.643 P 0.781 0.013 0.762 0.019

Table 4: Comparison of joint tenderness scores before and after treatment between two groups (points,±s)

Table 4: Comparison of joint tenderness scores before and after treatment between two groups (points,±s)

groups n Before treatment After treatment t P Tc-MDP group 116 45.62±6.01 15.29±4.61 29.472 0.000 zoledronic acid group 116 45.02±5.22 25.02±3.76 19.001 0.000 t 0.433 10.022 P 0.544 0.000

3. Results

3.1 Total efficiency comparison

The total effective rates of the zoledronic acid group and Tc-MDP group were 99.1% and 90.0%, respectively, and the zoledronic acid group were significantly higher than the Tc-MDP group (P＜0.05). Table2.

3.2 Bone mineral density comparison

The bone mineral density of lumbar vertebrae and hip after treatment were significantly higher than that of the two groups before treatment, and the zoledronic acid group were also significantly higher than the Tc-MDP group(P＜0.05). Table 3:

3.3 Comparison of joint tenderness scores

The joint tenderness scores of the two groups were significantly lower than those before treatment, and the Tc-MDP group were also significantly lower than the zoledronic acid group (P＜0.05). Table 4:

3.4 Comparison of changes in hematological indicators

There were no significant differences in serum calcium and blood phosphorus levels compared between the two groups (P＞0.05), and the erythroeyte sedimentation rate (ESR) levels were lower than before treatment (P＜0.05), The ESR levels of the Tc-MDP group were also significantly lower than that of the zoledronic acid group (P＜0.05). Table 5:

4. Discussion

Osteoporosis is a systemic disease, and its pathological phenomena include reduced bone mass and degradation of the fine structure of bone tissue, which are more common in the elderly [14]. The specific pathogenesis of the disease is not clear, and the etiology is related to gender, age, race, occupation, body mass index, excessive exercise, etc. [15]. Its onset process begins with uneven bearing load on the articular surface. Long-term osteoporosis can damage the articular cartilage or degrade its function, thereby accelerating the chronic pathological changes of the joint [16]. The treatment of this disease is to increase bone density, relieve joint pain, and control the development of the disease. The treatment drugs mainly include bone resorption inhibitors and calcium. Zoledronic acid can selectively congregate at the site of active bone resorption, causing osteoclasts to lose their function and eventually die. They are taken up by osteoclasts during bone resorption, which can show a strong and durable anti-osteoporosis effect. . However, its onset is slow and there is some drug resistance after long-term use [17-18].

Yunke is a drug with intellectual property protection in China, which can treat various orthopedic diseases including bonerelated complications caused by tumor bone metastasis and osteoporosis [19]. Yunke has strong chelating ability to metal ions, has strong anti-inflammatory and analgesic effects, can bind with hydroxyapatite crystals in bones in the body, and adsorbs on the surface of hydroxyapatite crystals, which can reduce metal Protease activity prevents collagenase from destructing and destroying articular cartilage and inhibits prostaglandin production [20]. It can also prevent the differentiation of bone marrow stem cells into osteoclasts, increase the number of osteocytes and promote the growth of new bones, repair damaged cartilage tissue, and play a longer role, which can restore joint function continuously [21]. This study showed that the total effective rates of the zoledronic acid group and Tc-MDP group were 99.1% and 90.0%, respectively, and the zoledronic acid group were significantly higher than the Tc-MDP group (P＜0.05). The bone mineral density of lumbar vertebrae and hip after treatment were significantly higher than that of the two groups before treatment, and the zoledronic acid group were also significantly higher than the Tc-MDP group(P＜0.05). It shows that both drugs have a better therapeutic effect. Among them, theapplication of zoledronic acid can more effectively promote the increase of bone density in patients and improve the prognosis of patients. Generally, we determine whether patients have osteoporosis based on bone density. However, it is worth noting that the bone mineral density value of the human body is not constant. In the human body's metabolic circulation system, the bone density value is usually determined by the two values of peak bone mass and bone loss rate. Changes in bone mineral density of patients should be detected at any time during treatment [22-23]. The so-called primary osteoporosis is a degenerative skeletal disorder that occurs with age. It is a naturally occurring physiological process. The main disorder is bone loss, bone formation is less than bone resorption, and the microstructure of bone is affected. When it is damaged, the toughness of the bone is reduced, the bone fracture is the worst, and even the disability can be caused [24]. Modern research suggests that the etiology of osteoporosis is complex and affected by many factors [25]. Bisphosphonates are stable analogs of pyrophosphates, which can change the properties of the bone matrix activated by osteoclasts, and can also selectively form high-depth drugs on the bone surface, hindering the activity of osteoclasts, and thus osteoclasts. Unable to activate, thus unable to connect to start other cells [26]. Yunke can combine with the hydroxyapatite crystals in the bone in the body, and has a longer acting time, can promote the division and proliferation of bone cells and the formation of new bone, and hinder the contact of osteoclasts and bone minerals, thus exerting a strong Anti-bone resorption capacity [27].This study showed that the joint tenderness scores of the two groups were significantly lower than those before treatment, and the Tc-MDP group were also significantly lower than the zoledronic acid group (P＜0.05). It shows that Yunke's application can more effectively improve the joint tenderness of patients. Current research shows that Yunke will be adsorbed on the surface of hydroxyapatite crystals (located in bone tissue) in the human body, which can hinder the decomposition of phosphatase and thus relieve bone pain. And Yun Ke combined with calcium and active vitamin D can be functionally complementary, thereby continuously improving the prognosis of patients [28].

Table 5: Comparison of changes in hematological parameters before and after treatment between two groups (±s)

Table 5: Comparison of changes in hematological parameters before and after treatment between two groups (±s)

groups n Blood calcium(mmol/L) Before treatment After treatment t P Blood phosphorus(mmol/L) Before treatment After treatment t P ESR(mm/h) Before treatment After treatment t P Tc-MDP group 116 2.24±0.10 2.27±0.19 0.231 0.764 1.03±0.13 0.99±0.09 0.722 0.211 27.44±8.24 14.76±3.42 22.993 0.000 zoledronic acid group 116 2.21±0.08 2.20±0.15 0.144 0.795 1.05±0.09 1.00±0.08 0.633 0.311 26.98±7.13 20.14±3.19 11.222 0.000 t 0.244 0.422 0.294 0.144 0.652 11.663 P 0.689 0.566 0.244 0.000

Blood calcium, blood phosphorus, and ESR play an important role in the osteolytic cytokine network of the bone tissue microenvironment in the bone metabolism regulation system, can promote bone growth and reconstruction, and have important significance for the process of bone metabolism regulation [29]. Improper application of drug treatment can lead to an increase in blood calcium and blood phosphorus levels, which in turn promotes osteoclast cell activity to become mature, and affects the activity of osteocyte alkaline phosphatase, increasing the risk of fracture [30]. The high content of ESR can directly stimulate bone resorption, but also enhance the effects of other cytokines, enhance bone resorption, and is not conducive to improving the prognosis of patients. Yunke has good targeting for bone tissue, and the bisphosphonic acid compound has a high affinity for mineralized bone, which can show stronger binding force with hydroxyapatite on the bone surface, and have a stronger ability to reduce osteoclasts. The role of activity [31]. Yunke has good targeting for bone tissue, and has the effect of scavenging free radicals in the body and inhibiting the production of pathological complexes [32-33].This study showed that there were no significant differences in serum calcium and blood phosphorus levels compared between the two groups (P＞0.05), and the erythroeyte sedimentation rate (ESR) levels were lower than before treatment (P＜0.05), The ESR levels of the Tc-MDP group were also significantly lower than that of the zoledronic acid group (P＜0.05). It shows that Yunke and zoledronic acid do not affect the body's blood calcium and blood phosphorus content, and the application of Yunke can reduce the body's ESR content. Current research shows that Yunke can inhibit the body from inhibiting the release of inflammatory factors, thereby enhancing the body's ability to resist osteoporosis, and delaying the development of inflammatory lesions and tissue damage [34-35-36]. This study also has certain shortcomings. The research sample is relatively small, and there is no long-term follow-up study. Only short-term treatment effects of the two drugs can be obtained. Further large clinical samples and long-term follow-up studies are needed in the future.

The zoledronic acid and the application of Tc-MDP in the treatment of osteoporosis can increase bone density, relieve joint tenderness symptoms, reduce ESR content, and will not affect patients' blood calcium and blood phosphorus levels. However, zoledronic acid increases bone density significantly are better than the Yunke, and Yunke relieves joint pain significantly are more than zoledronic acid.