Effects of vitamin D with or without calcium on pathological ossification: A retrospective clinical study
- Authors:
- Published online on: February 15, 2022 https://doi.org/10.3892/etm.2022.11214
- Article Number: 285
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Copyright: © Liang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Osteoarthritis (OA) is a common degenerative disease of the joints; it is characterized by the destruction of articular cartilage, often accompanied by hypertrophy of chondrocytes and calcification, resulting in the formation of new bones (osteophytes) or cartilage ossification bands on the edge of the joints (1). This pathological ossification is also common in other rheumatic diseases, including rheumatoid arthritis (RA) and spondylarthritis (SA) (2). In addition, ectopic osteogenesis is frequently observed in spinal ligaments, including the posterior longitudinal ligament and ligamentum flavum (3). The abnormal ossification of joints clinically causes pain, movement disorders and joint deformation, and the ossification of spine ligaments compresses the spinal cord or nerve roots, which leads to various degrees of neurological symptoms (3). Besides surgical treatment, no effective strategy has been indicated to promote the regression of abnormal ossification.
Vitamin D plays a pivotal role in maintaining calcium and phosphate homeostasis, as well as in regulating bone metabolism; it undergoes bioconversion to an active form called 1,25-dyhydroxyvitamin D [1,25(OH)2D)], which elicits its biological functions through vitamin D receptor (VDR) (4). Activation of VDR promotes absorption or resorption of calcium and phosphorus in the intestine and renal tubules, and regulates parathyroid hormone secretion (4). These functions can indirectly regulate bone growth and mineralization. In addition, vitamin D directly acts on bone growth and mineralization, as well as in bone remodeling (5). Accumulating evidence has demonstrated that vitamin D exerts opposing effects on bones, such as anti-resorptive and pro-resorptive effects (6). Previous in vitro and in vivo experiments have demonstrated that higher concentrations/doses of vitamin D stimulate osteoclastic bone resorption (6). In addition to regulating calcium and phosphate metabolism, vitamin D is also known as an immunomodulatory hormone, and thus aids in the protection against the development of various severe rheumatic diseases, including OA, RA and SA (7-9). However, the effect of vitamin D on pathological ossification associated with rheumatic diseases remains unknown. Based on the pro-resorptive action of vitamin D, it was speculated that high doses of vitamin D may produce ameliorative effects on pathological ossification. In addition, calcium is usually employed in combination with vitamin D for the treatment of rheumatic diseases. Calcium directly promotes osteoblast to osteocyte transition and thus stimulates bone mineralization (10). Whether calcium supplementation affects the action mode of vitamin D is also unknown. The aim of the present study was to compare the clinical outcomes of using vitamin D alone and vitamin D with simultaneous calcium supplementation on the pathological ossification associated with several rheumatic diseases.
Materials and methods
Study design
In the present retrospective study, data were collected from patients of either sex who had been diagnosed with OA, RA or SA at an age range of 18 to 75 years, in whom abnormal ossification in the joints and vertebral bodies, as well as in the spinal ligaments (posterior longitudinal ligament or ligamentum flavum), was confirmed by X-ray, computed tomography or magnetic resonance imaging examination. Patients were examined in Qiaoxi Tong-Xinglong Western Medicine Clinic (Shijiazhuang, China) between January 2010 and December 2019. All patients in the present study received 300,000 IU vitamin D intramuscularly, once every 7-10 days, 4-6 times in total. Patients receiving additional oral calcium administration (1,000 mg/day; ≥5 days/week) were defined as the vitamin D with calcium group. The remaining patients were defined as the vitamin D only group. The total period of treatment was 1-2 months. All patients provided written informed consent before receiving vitamin D. Exclusion criteria prior to and during the study included the following: i) Medical conditions or disorders that influence bone mineral metabolism; ii) obvious clinical symptoms associated with severe organ diseases (including heart, liver, kidney, lung, digestive tract and thyroid) or other metabolic diseases, which required specific therapeutic interventions for >1 week; and iii) patients who did not receive ≥4 injections of vitamin D. The imaging examination was performed before treatment and within 1 month of treatment. The primary endpoint was evaluated based on the imaging changes of pathological ossification, which were classified into three types of outcomes: i) Alleviation; ii) aggravation; and iii) unchanged. Evaluation of imaging changes was performed by two radiologists and an orthopedic surgeon.
Bone mineral density (BMD) determination
BMD was determined in 141 patients in the vitamin D alone group and 135 patients in the vitamin D and calcium group at the lumbar spine (L1-L4) and the left femoral neck before and after vitamin D treatment via dual energy X-ray absorptiometry (Hologic Discovery-A; Hologic Canada ULC); as a measurement of precision, the coefficient of variation was <1%.
Biochemical analysis
The levels of calcium and phosphorus in serum and urine were determined in 31 patients in the vitamin D alone group and 32 patients in the vitamin D and calcium group. Blood and urine samples were collected in the morning after overnight fasting, and serum and urinary concentrations of total calcium and phosphorus were measured using an automatic biochemical analyzer (AU5400; Olympus Corporation).
Safety assessment
Adverse reactions reported by the patients were collected. Changes in physiological parameters, including vital signs and electrocardiogram readings, were recorded in 40 patients in the vitamin D alone group and 36 patients in the vitamin D and calcium group; biochemical blood analyses including alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), total protein (TP), urea nitrogen (BUN) were performed in 18 patients in the vitamin D alone group and 17 patients in the vitamin D and calcium group. In addition, some patients underwent ultrasound examination of abdominal organs and neck vasculature before and after treatment.
Statistical analysis
The number of patients (percentage) were used to describe patients' clinical characteristics and the χ2 test was applied to evaluate the efficacy difference between two groups. Quantitative data including BMD, biochemical parameters and levels of calcium and phosphorus were presented as the mean ± SD unless stated otherwise and the differences were evaluated using paired Student's t-test for single repeated measurements or unpaired Student's t-test for comparison of changes between two groups. Data analysis was performed with SPSS version 20 (IBM Corp.). P<0.05 was considered to indicate a statistically significant difference.
Results
Clinical outcomes
A total of 2,965 patients were included in the present study, among who, 1,725 were in the vitamin D alone group and 1,240 were in the vitamin D with calcium group. Joint pathological ossification primarily occurred in the cervical and lumbar spine, knee, elbow, ankle, wrist and finger joints. Spinal ligament (posterior longitudinal ligament and ligamentum flavum) ossification was also observed. The outcomes of the two regimens on the pathological ossification associated with OA and other types of diseases were separately analyzed. There was no significant difference in sex, age or ossification sites between the vitamin D alone and vitamin D with calcium groups (Table I). Considering the possible impact of age-related dietary calcium intake on the study, the populations <40 and ≥40 years of age were separately analyzed. In the population <40 years of age, 54% (123/228) of patients with OA in the vitamin D alone group exhibited alleviation, 18% (42/228) exhibited aggravation and the remaining 28% (63/228) presented with unchanged symptoms (Table II). By contrast, only 3% (5/185) of subjects in the vitamin D with calcium group showed alleviation [risk ratio (RR), 1.741; 95% confidence interval (CI), 1.585-1.912; P<0.0001], while 66% (122/185) showed aggravation (RR, 0.464; 95% CI, 0.352-0.611; P<0.0001) and 31% (58/185) presented with unchanged symptoms (RR, 0.943; 95% CI, 0.779-1.143; P=0.6039). Similar outcomes were obtained in patients with RA and SA. Vitamin D alone resulted in 64% (209/327) alleviation, while vitamin D combined with calcium aggravated the ossification in 69% (188/274) (RR, 0.309; 95% CI, 0.229-0.416; P<0.0001). Comparable therapeutic outcomes on pathological ossification in the population ≥40 years of age were observed. For OA-associated pathological ossification, treatment with vitamin D alone resulted in 70% (426/609) alleviation, 10% (59/609) aggravation, and 20% (124/609) unchanged; whereas vitamin D combined with calcium led to 64% (171/266) aggravation (RR, 0.369; 95% CI, 0.295-0.461; P<0.0001), 7% (18/266) alleviation (RR, 1.379; 95% CI, 1.314-1.446; P<0.0001), and 30% (77/266) unchanged (RR, 0.886; 95% CI, 0.788-0.997; P=0.0357) (Table III). Similar results were observed for RA- and SA-associated pathological ossification (Table III). The representative imaging alterations for ‘alleviation’ in the vitamin D alone group and ‘aggravation’ in the vitamin D with calcium group are demonstrated in Figs. S1 and S2, respectively. The results indicated that vitamin D alone promoted the resorption of abnormal ossification, whereas vitamin D combined with calcium aggravated the ossification in the majority of patients, independently of the disease type.
 | Table IBaseline characteristics of patients included in the vitamin D alone (n=1,725) and vitamin D with calcium (n=1,240) groups. |
| Table IIClinical outcomes of vitamin D alone (n=555) and vitamin D with calcium (n=459) groups on the pathological ossification in patients <40 years old. |
| Table IIIClinical outcomes of vitamin D alone (n=1,170) and vitamin D with calcium (n=781) groups on the pathological ossification in patients ≥40 years old. |
It was noted that, for OA-associated abnormal ossification, vitamin D alone treatment resulted in 70% alleviation in the population of ≥40 years of age (Table III), which was significantly higher than that observed in patients <40 years of age (54%; Table II) (P<0.05). This may be due to a higher calcium intake in the diet of young individuals compared with that in the elderly (11). In addition, the treatment regimen of vitamin D was slightly different among patients who received intramuscular injection once every 7 to 10 days for 4 to 6 times since it was not applicable to choose patients with exact same and times in this retrospective analysis. This study revealed that the slight variance of vitamin D application time and frequency did not affect the outcomes of treatments (data not shown).
BMD measurement results
Next, the effects of vitamin D with or without calcium on BMD were evaluated. Considering the possible differences in BMD in females, particularly in postmenopausal females, the data were separately analyzed according to patient sex and age. As presented in Table IV, there was no significant difference in BMD at the lumbar spine or femoral neck before and after treatment with vitamin D with or without calcium among different sex or age groups. However, vitamin D alone produced a decreasing trend in BMD in different sex and age groups, whereas vitamin D with calcium demonstrated an increasing trend in BMD.
Biochemical analysis results
Biochemical analysis indicated that the serum calcium concentration did not change after the administration of vitamin D alone in males or females, but the urine calcium concentration was significantly increased in both sexes (both P<0.05), suggesting an increase in calcium excretion (Table V). Vitamin D alone did not significantly alter serum or urinary phosphorus levels. Vitamin D with calcium exhibited no significant effect on calcium or phosphorus levels in either the serum or urine (Table V).
Drug safety assessment
Due to the high dose of vitamin D used in the present study, its safety was evaluated. No serious adverse reactions were reported from any of the participants during treatment or the follow-up period of observation. Changes in physiological parameters, including body temperature, heart rate, RR, blood pressure and blood glucose, and adverse reactions such as arrhythmias and cardiac ischemia, are presented in Table SI. The number of subjects with positive changes or with adverse reactions did not notably differ between the two groups. In addition, subjects in the vitamin D with or without calcium groups exhibited no significant alterations in the blood biochemical parameters including ALT, AST, CK,TP and BUN, which reflecting functional changes in the heart, liver and kidney (Table SII). A total of 18 patients (10 males and 8 females) in the vitamin D alone and 17 patients (8 males and 9 females) in the vitamin D with calcium group underwent ultrasound examination of the abdominal organs and neck vasculature before and after treatment in order to detect heterotopic ossification of the soft tissues. There was no new ossification in the abdominal organs or neck vessels of the patients treated with vitamin D alone, whereas abdominal ultrasound examination of subjects treated with vitamin D with calcium revealed an aggravated prostate ossification in one subject, a novel prostate ossification in another subject and a suspected kidney stone in a female patient. Cervical vascular ultrasound examination revealed a calcified plaque of the common carotid artery in a male patient and an aggravated calcified plaque of an internal carotid artery in a female patient.
Discussion
The main findings of the present clinical study were that vitamin D alone produced an improvement in the pathological ossification of joints or ligaments, whereas vitamin D in combination with calcium exhibited an opposing clinical outcome with aggravation of this ossification. Similar results were observed in subjects with different ages and were irrespective of the disease type. In addition, vitamin D alone tended to reduce BMD in normal bone, while vitamin D with calcium tended to increase BMD. These results indicated that a high dose of vitamin D alone may have pro-resorptive action, whereas vitamin D combined with a calcium supplement may promote osteogenesis.
At present, the direct action of the VDR in bone tissue is not well understood. It is widely accepted that vitamin D is important for bone growth, as its deficiency can lead to osteomalacia and rickets (4,5). However, the direct effects of vitamin D on bone remain under debate. A previous study has demonstrated that 1,25(OH)2D stimulates osteoclast formation in the co-culture of mouse osteoblastic and hematopoietic cells (12). Osteoclast precursors express receptor activator of nuclear factor-κB (RANK) and they recognize RANK ligand (RANKL), and differentiate into osteoclasts (13). In addition, 1,25(OH)2D increases RANKL expression in osteoblast-lineage cells, thus stimulating bone resorption through VDR expressed in osteoblast-lineage cells (14-16). Previous experiments have revealed that high-dose administration of 1,25(OH)2D inhibits the mineralization of osteoblasts (17,18). These findings have suggested that a high dose of vitamin D may suppress osteoblastogenesis and stimulate bone resorption. It is generally accepted that the molecular mechanisms underlying pathological or ectopic ossification of joint or soft tissues are similar to those regulating the physiological ossification of skeletal tissues (1). Consistent with the aforementioned results, the present study revealed that a high dose of vitamin D alone alleviated pathological ossification of the joints and ligaments, with a trend in the reduction of BMD in normal bone. These results suggest that pathological ossification may be more sensitive to the pro-resorptive action of vitamin D than normal bone. It is known that vitamin D promotes bone resorption and can increase blood calcium levels (15). However, the present study did not find a significant increase in blood calcium; only a higher urine calcium concentration was observed. The increased urinary calcium excretion may maintain blood calcium homeostasis.
Notably, the present study revealed that vitamin D in combination with calcium supplementation resulted in the deterioration of pathological ossification, with a tendency for increased BMD in normal bone, while calcium supplementation reversed the action model of vitamin D, namely from a pro-resorptive to an anti-resorptive effect. The mechanism underlying the regulation of exogenous calcium supplementation on the bidirectional effect of vitamin D is unknown. Previous evidence has demonstrated that calcium per se promotes osteoblast to osteocyte differentiation, inhibits the activation of osteoclasts and promotes bone mineralization in a concentration-dependent manner (10,19). It can be hypothesized that in the presence of a sufficient quantity of calcium supplement, extraosseous action of vitamin D such as the promotion of the intestinal absorption of calcium and renal calcium resorption may make it predisposed to promote osteogenesis and bone mineralization. In addition, the results may also be secondary responses to the change of cytokines, since vitamin D has an immunomodulatory action (7-9). One of the limitations to the present study is that serum levels of inflammatory cytokines were not determined. The detailed mechanism underlying the bidirectional effect of vitamin D requires further elucidation.
Regarding the safety of vitamin D administration, the present study showed that 300,000 IU vitamin D administered intramuscularly every 7-10 days for a total of 4-6 times did not induce serious adverse reactions in any of the subjects. Vitamin D toxicity has been previously observed in patients who received multiple intramuscular injections of vitamin D, each containing 600,000 IU vitamin D (20). Thus, safety should be considered for the prolonged usage of vitamin D.
In conclusion, to the best of our knowledge, the present study demonstrated for the first time that vitamin D alone or in combination with calcium exhibited ameliorative or deteriorative effects, respectively, on pathological ossification. Although the mechanism by which vitamin D exerted biphasic and opposing effects on bone remains to be clarified, the results of the present study provided an important reference for the treatment of pathological ossification-related diseases and osteoporosis. Pathological ossification is an important feature in OA progression (1,21). Inhibiting pathological ossification represents a potential therapeutic target in the management of OA. The present results suggest that vitamin D alone could promote the resorption of abnormal ossification and thus alleviate clinical symptoms, such as pain caused by bone spurs and the prevention of exercise. However, the balance of benefits and risks should be considered. The present study demonstrated that the treatment period should not exceed 2 months so that it has less impact on normal bone BMD. In addition, although vitamin D is widely used in the treatment of osteoporosis and the prevention of fractures from falls, clinical trials of various cohort sizes have so far failed to obtain consistent positive results (22-24). Previous studies in which vitamin D was administered as bolus doses reported significant increases in fractures and falls (25). A recent study indicated that 3 years of high-dose vitamin D supplementation (400, 4,000 and 10,000 IU) in healthy, vitamin D-sufficient individuals aged 55-70 years old resulted in a negative dose-response association with bone density and strength (26). The findings of the present study provide an explanation for the inconsistent or even contrary clinical outcomes of vitamin D treatment. It is necessary to optimize the dose, protocol and use of simultaneous calcium supplementation when applying vitamin D for the treatment of osteoporosis.
Supplementary Material
Representative imaging demonstrating the abnormal ossification of the joints or ligaments before treatment and the alterations observed after treatment with vitamin D alone. Abnormal ossification is indicated by arrows. (A) A 60-year-old female patient with osteoarthritis (OA). Before treatment, the physiological curvature of the cervical vertebrae was changed on X-ray examination, with abnormal ossification in the C2-C7 intervertebral space, mild spondylolisthesis in the C6 and C7 vertebral bodies and olecranoid hyperplasia in the anterior margin of the C6 and C7 vertebral bodies. After medication, the abnormal ossification regressed, the olecranon hyperplasia became blunt, the C6 spondylolisthesis improved, and the curvature of the cervical spine returned to normal. (B) A 52-year-old male patient with spondylarthritis (SA). The C2-C7 intervertebral space was blurred due to abnormal ossification, which was alleviated after treatment. (C) A 50-year-old male patient with OA. Computed tomography (CT) images indicated osteophyte formation on the posterior upper margin of the C7 and T1 vertebral bodies. After treatment, the osteophyte formation was notably reduced, and a posterior joint space appeared. (D) A 72-year-old female patient with SA. The lateral radiograph of the lumbar spine demonstrated multiple intervertebral abnormal ossifications before treatment, which were alleviated, and the intervertebral space was widened after medication. (E) A 52-year-old male patient with OA. X-rays revealed bone spurs on both sides of the L4 vertebral body and hypertrophy of the transverse processes on both sides of the L5 vertebral body, which fused with the iliac crest. After medication, the bone spurs became blunt, the hypertrophic transverse processes were reduced, and a joint space appeared between the L4 vertebral body and the iliac spine. (F) A 76-year-old male patient with OA. Severe ossification was observed in the medial space of the left knee joint, with abnormal ossification in the intercondylar ridge. After medication, the abnormal ossification in the medial space was obviously regressed. (G) A 72-year-old female patient with rheumatoid arthritis (RA). X-ray revealed abnormal ossification in the knee joint. After treatment, the abnormal ossification was alleviated, and the joint space was widened with reduced intercondylar ridge. (H) A 64-year-old female patient with OA. X-rays demonstrated abnormal ossification in the knee joint. After treatment, the abnormal ossification was regressed, and the subluxation of the joint was improved. (I) A 27-year-old female patient with RA. X-rays indicated abnormal ossification in the right knee joint cavity. After treatment, a bilateral space appeared. (J) A 47-year-old male with RA. X-rays revealed severe ossification and stenosis of the knee joint space. After treatment, the abnormal ossification was alleviated, and the bilateral joint space was evident. (K) A 42-year-old male patient with OA. X-ray examination demonstrated abnormal ossification of the elbow joint and formation of osteophytes in the olecranon, radial head and coronoid process. After treatment, regression of abnormal ossification was observed. (L) A 38-year-old female patient with RA. Abnormal ossification was visible in the carpometacarpal wrist joint, which regressed after treatment. (M) A 37-year-old female patient with RA. There was abnormal ossification in the space of the finger joints. Regression of the calcified joints was observed after medication. (N) A 45-year-old female patient with SA. CT imaging demonstrated abnormal ossification of the L3/L4 posterior longitudinal ligament, which was alleviated after treatment. (O) A 51-year-old female patient with SA. CT imaging revealed abnormal ossification of the ligamentum flavum on both sides of L4/L5, particularly on the left side. After medication, regression of abnormal ossification could be observed. (P) A 23-year-old male patient with SA. CT imaging indicated L4/L5 disc herniation combined with strip abnormal ossification of the posterior longitudinal ligament. After treatment, the strip abnormal ossification disappeared. (Q) A 50-year-old male patient with SA. CT imaging demonstrated abnormal ossification of the right lateral recess of the L5/S1 ligamentum flavum, which regressed after treatment. OA, osteoarthritis; SA, spondylarthritis; CT, computed tomography; RA, rheumatoid arthritis.
Representative imaging demonstrated the pathological ossification of the joints or ligaments before treatment and the alterations observed after treatment with vitamin D combined with calcium. Abnormal ossification is indicated by arrows. (A) A 42-year-old female patient with OA. X-ray images demonstrated mild hyperplasia at the posterior and upper edge of the C3-C6 vertebral bodies. After medication, the abnormal ossification at the C3-C6 vertebral bodies was aggravated. (B) A 35-year-old male with SA. X-rays showed mild bone hyperplasia at the posterior and upper edge of the C3-C5 vertebral body, which was aggravated after medication. (C) A 45-year-old male patient with OA. X-rays revealed that the L3/L4 space was narrow due to abnormal ossification, which was aggravated after medication. (D) A 61-year-old female patient with OA. X-rays indicated a slight narrowing of the medial space in the knee joints. After medication, the abnormal ossification was aggravated, and the joint space became narrower. (E) A 60-year-old male patient with OA. The joint space of the right elbow was calcified, which was aggravated after medication. (F) A 38-year-old male patient with RA. Abnormal ossification was observed in the ankles. After medication, the joint space became narrower. (G) A 62-year-old male patient with RA. Abnormal ossification of the proximal phalangeal joint was obvious and was aggravated after medication. (H) A 66-year-old male with OA. Lateral X-ray imaging revealed hyperosseous bone in the right ankle, and abnormal ossification worsened after medication. (I) A 48-year-old male patient with SA. Lumbar computed tomography demonstrated left herniation of the L4/L5 disc. After medication, the herniated disc was constricted, but abnormal ossification was visible at the left posterior longitudinal ligament. (J) A 64-year-old female patient with SA. Magnetic resonance imaging demonstrated abnormal ossification of the ligamentum flavum C1-C7 after medication. OA, osteoarthritis; RA, rheumatoid arthritis.
Changes of physiological parameters and incidence of adverse reactions.
Determination of serum biochemistry before and after treatments.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
LL participated in the data collection and analysis. TT participated in the assessment of images. LQ and JX participated in the data analysis, and YX, YQ, LZ, DL and XN participated in acquisition of patients' data. XT designed and conceptualized the study, drafted the manuscript and contributed to interpretation of the data. LL and XT confirm the authenticity of all the raw data. All authors have read and approved the final version of the manuscript.
Ethics approval and consent to participate
The present study was approved by the Ethics Committee of Hebei Xinglong Institute of Pharmaceutical and Medical Science (Shijiazhuang, China; approval no. XLEC200901). Written informed consent was obtained from all patients prior to treatment.
Patient consent for publication
Written informed consent for the publication of any data and accompanying images was obtained from the patients.
Competing interests
The authors declare that they have no competing interests.
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