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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 3  |  Issue : 2  |  Page : 227-233

Role of bisphosphonates in management of osteoporosis and its adverse effects on the jaw


1 Department of Pedodontics and Preventive Dentistry, Shri Guru Ram Das Dental College, Amritsar, Punjab, India
2 Private Hospital, Amritsar, Punjab, India
3 Dental Surgeon, Private Dental Clinic, Amritsar, Punjab, India
4 Government Medical College, Amritsar, Punjab, India

Date of Web Publication16-Dec-2015

Correspondence Address:
Prabhnavroop Singh Chatha
Dental Surgeon, Private Dental Clinic, 6/4 College Lane, Rani ka bagh, Amritsar - 143 001, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2321-4848.171910

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  Abstract 

Background: The efficacy of different types of bisphosphonates has already been established in the treatment of osteoporosis and some studies have also shown some correlation to its side effects on oral health. Aim and Objective: To determine the role of different bisphosphonate drugs (inhibitor osteoclast-mediated bone resorption) in the treatment osteoporosis and their adverse effects jaw under one study over a period of 24 months. Materials and Methods: This is a longitudinal study of selected patients and the changes were studied during follow-ups that were designed at 6, 9, 12, 24 months. Four groups (16 patients in each) were formed with patients undergoing treatment for osteoporosis and were administered different bisphosphonates group medicine (Alandronate- short acting; Ibandronate- medium acting; Zoledronic acid- long acting) and effects and side-effects on jaw were studied during follow-up. Results: After 2 years, the patients receiving bisphosphonates (groups A, B, C) had significant increase in their mean (±SE) spinal bone density (4.2 ± 0.8% and 5.2 ± 0.7%, respectively; P < 0.017). The rate of new vertebral fractures was reduced by half in the bisphosphonate-treated patients as compared with the patients who only received calcium and vitamin Db (group D) (29.5 vs. 62.9 fractures per 1,000 patient-years; P = 0.043); also there were seen osteonecrosis-like symptoms in jaw more in zoledronic-acid-using patients and as compared to oral bisphosphonates. Conclusion: Bisphosphonate therapy for 2 years significantly increases spinal bone mass and reduces the incidence of new vertebral fractures in osteoporotic patients, but also has risk factor for jaw bone necrosis associated with it.

Keywords: Bone mineral density, clinical attachment level, standard deviation


How to cite this article:
Sadana G, Singh R, Chatha PS, Kaur S. Role of bisphosphonates in management of osteoporosis and its adverse effects on the jaw. Arch Med Health Sci 2015;3:227-33

How to cite this URL:
Sadana G, Singh R, Chatha PS, Kaur S. Role of bisphosphonates in management of osteoporosis and its adverse effects on the jaw. Arch Med Health Sci [serial online] 2015 [cited 2019 Sep 19];3:227-33. Available from: http://www.amhsjournal.org/text.asp?2015/3/2/227/171910


  Introduction Top


Osteoporosis is a disease of bones that leads to an increased risk of fracture. [1] In osteoporosis, the bone mineral density (BMD) is reduced, bone microarchitecture deteriorates, and the amount and variety of proteins in bone are altered. Osteoporosis is defined by World Health Organization (WHO) as a bone mineral density of 2.5 standard deviations or more below the mean peak bone mass (average of young, healthy adults) as measured by dual-energy X-ray absorptiometry.

The purpose of this longitudinal study is to show role and importance of oral and I.V. administered bisphosphonates in management of osteoporosis and also to shed light on their adverse effects on jaw bone.

Bisphosphonates approved to prevent and/or treat osteoporosis

There are many drugs used now which have been introduced over time. Drugs like bisphosphonates group have proven their medical efficacies along with other groups like estrogen hormone regulating ones in women with post-menopausal cause of osteoporosis. Drugs available and used in the treatment have been summed up in [Table 1]. [17]
Table 1: Bisphosphonates approved to prevent and/or treat osteoporosis

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  Materials and Methods Top


Patients

Under this longitudinal study program conducted over a time period of 24 months, 64 eligible patients participated. The eligibility of the patients participating were post-menopausal women between the ages of 55 years and 86 years who had a bone mineral density T score of −2.5 standard deviation (SD) or less at the femoral neck, with or without evidence of existing vertebral fracture, or a T score of −1.5 SD or less, with radiologic evidence of at least two mild vertebral fractures or one moderate vertebral fracture and had not used bisphosphonates in last 2 years (washout period). Ineligibility criteria included any previous use of parathyroid hormone or sodium fluoride, use of anabolic steroids or growth hormone within 6 months before trial entry or oral or intravenous systemic corticosteroids within 12 months, and any previous use of strontium. Males with osteoporosis i.e., bone mineral density at the femoral neck that was at least 2 SD below the mean value and at least one vertebral deformity or a history of an osteoporotic fracture.

Study design

This study was conducted as a part of normal routine follow-up of patients coming to a private orthopedic clinic for management of osteoporosis for time period of study November 2011 to December 2013.

This is a longitudinal study of selected patients and the changes were studied on follow-ups that were designed at 6, 9, 12, 24 months. The 3-month's interval was chosen to study the effects in detail of short acting bisphosphonates as along with the long acting ones and routine dental check up was performed to at the follow-up. There were formed four groups of patients undergoing treatment for osteoporosis, each group had 16 patients that were administered different bisphosphonate medicines. These were prescribed according to patient and doctor compliance for the treatment of osteoporosis and their effects were studied during follow-up.

The patients were assigned to four main groups based on the examination at the base line and the prescribed drug for their therapy according to patient compliance. The four groups were.

Group A: Prescribed drug for therapy was Alendronate (Oral - tablet 70mg) to be taken once every week

Group B: Prescribed drug for therapy was Ibandronate (oral tablet 150 mg) to be taken once every month

Group C: Prescribed drug for therapy is Zoledronic acid (5 mg) (15-minute intravenous administration) to be given once a year

Group D: Prescribed daily calcium + vitamin D (oral - 1250 mg +250 IU) (Recalvin- brand name). Patients in this group were either too poor to buy any costly medicine or were not ready to take any therapeutic medicine for osteoporosis treatment except calcium and Vitamin D which was provided to the patients free of cost by the contributors of this article

In addition, all patients in all the other groups were prescribed daily calcium + vitamin D (oral -1250 mg +250 IU)

Patients were instructed to take Ibandronate or Alendronate in the morning, after an overnight fast, in an upright position and with a full glass of plain water. Patients were to remain fasting and in an upright position for at least 30 or 60 min after dosing with Alendronate and Ibandronate, respectively. Concomitant treatment with calcium and Vitamin D was permitted with the Recalvin.

Base line and follow-up studies

At base line a complete history was obtained, and each subject underwent a physical examination, electrocardiography, and chest radiography.

Medical evaluation

At each clinic visit, the patients were questioned about symptoms. At each designated study follow-up height was also measured in triplicate with a stadiometer (Harpenden, Holtain, Crymmych, Pembrookshire, UK). If any two of the measurements differed by 4 mm or more, two additional measurements were obtained. Bone mineral density was measured at base line and at 6, 9, 12, and 24 months. Radiographic assessment was also made at baseline then at 12 and 24 months. Posteroanterior and lateral radiographs of the lumbar and thoracic spine were obtained to detect any vertebral fractures and extent of vertebral deformity. Laboratory analyses, including hematologic tests and tests of renal and liver function and other biochemical markers, at base line.

Dental evaluation

Total number of teeth present at base line and at follow-up were co-related with any dental treatment patient underwent during the study. Clinical attachment level (CAL) of gingiva was measured and Periodontitis if present was noted and recession measured with respect to Cemento-enamel junction with WHO probe and same was measured at follow-up. In denture-wearing patients, the oral mucosa was examined only for any visible red or white lesions. Any relevant intra-oral periapical radiograph was taken in case of any suspected periapical or jaw lesion. All the patients were given standard oral hygiene instructions at each visit. Characteristics of patients recorded at base line are shown in [Table 2].
Table 2: Base line characteristics of patients

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Measurement of bone mineral density

The bone mineral density of the lumbar spine, hip, and total body was measured by dual-energy X-ray absorptiometry in the anteroposterior view (Hologic, Waltham, Mass, or Lunar, Madison, Wis.). To determine subjects' eligibility on the basis of their bone mineral density T scores the diagnoses of osteopenia and osteoporosis were made in accordance with the WHO criteria for postmenopausal women based on bone mineral density (BMD) T-scores. Osteopenia was diagnosed if the T-score was -1.0 to -2.5 and osteoporosis if the T-score was lowers than -2.5.

Radiographic assessment

To detect both vertebral fractures that were present at base line and those that occurred during the study, X-ray films were assessed by personnel who were unaware of the subjects' treatment assignment.

Radiographs of the spine obtained at base line and those obtained at 12 months and 24 months were available for analyses by semi quantitative methods in the case of 64patients. Painful vertebral fractures were identified when the patients sought medical attention for back pain and spinal radiographs demonstrated a new vertebral deformity. Non-vertebral fractures involving any skeletal site were reported by the subjects themselves and were confirmed by a review of radiographic records.

Biochemical measurements

For all patients' standard hematological and serum chemistry values were obtained from different lab tests at entry or base line and were checked at regular intervals during the study. Blood samples were collected after at least four-hours fast before the ingestion of the study drug. Urine (2 hours or 24 hours collection) was analyzed for Creatinine, Calcium, and Hydroxyproline concentrations at entry and during every follow-up, there after urine calcium and hydroxyproline levels were expressed relative to creatinine levels.

Statistical analysis

The results are expressed as the means ± SE and reflect results from all patients who began the study regimen. All statistical tests were two-sided. An assigned significance level of 0.05 was used except in efficacy analyses involving comparisons at multiple time points. The significance level of such analyses was adjusted by the Bonferroni method (i.e., 0.05 divided by the number of time points compared) to maintain an overall significance level of 0.05. Both actual and percent changes were evaluated when possible.

Two-way analysis of variance was used to test for clinics interactions in demographic and selected clinical results before the results compiled. The comparability of the four treatment groups at base line was tested by one-way analysis of variance. Changes from base line in bone-mass variables (bone mineral density and bone mineral content) were compared after 6, 9, 12, and 24 months by paired t-tests (intra-group) and one-way analysis of variance (intergroup). The method of linear contrasts was used to make paired comparisons: Group A versus group C, group A versus group D, group B versus group C, and group C versus group D.

Linear regression analysis by the zero-intercept model was used to calculate the slope of the percent change in bone mass of the spine and hip (Ward's triangle) plotted against time for patients who completed the study; a group mean slope (rate of change per year) was calculated from the estimates of the slopes for individual patients. Intergroup comparisons were performed by one-way analysis of variance.

Chi-square testing of two-by-two tables was used for intergroup paired comparisons of the number of patients with new vertebral fractures. For comparisons of the rates of new vertebral fractures (expressed as the number of fractures per 1,000 patient-years), Kruskal-Wallis analysis was used for four-group comparisons, and the Wilcoxon rank-sum test for two-group comparisons.

Biochemical variables of interest, with the exception of parathyroid hormone, were analyzed by paired t-tests (intra-group) and one-way analysis of variance (intergroup) at entry and after 24 months. Paired comparisons were performed by the method of linear contrasts.


  Results Top


Among the 64 patients that participated in the study, all completed the course of 24 months follow-up program at the clinic. As seen in the base line characteristics [Table 3] the groups at the entry were initially comparable. There were no significant intergroup differences at base line in the bone mineral density of the spine or other characteristics in the subgroups with low bone mineral density (data not shown).
Table 3: New vertebral fractures/deformities diagnosed during 24-month study

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Changes in bone mass

In all the bisphosphonate-treated groups (groups A, B, C), there were similar and significant increases from base line in the bone mineral density of the spine after 6, 9, 12, and 24 months (P < 0.017) [Figure 1].
Figure 1: Mean (±SE) changes in bone mineral density of the spine (as measured by dual-photon absorptiometry) in Group A (Alendronate, blue), Group B (Ibandronate, red), Group C (Zolidronic acid, green), and Group D (daily calcium and vitamin-D, purple)

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The mean (±SE) increase in group A and B (Alendronate and Ibandronate) after 24 months was 0.033 ± 0.006 g per square centimeter (4.2 ± 0.8%) and in group C (Zoledronic acid), 0.042 ± 0.006 g per square centimeter (5.2 ± 0.7%); these changes were significantly different from that in group D (Calcium and Vitamin D) (P < 0.01)

In general, there was an increase in bone mineral density of the hip from base line to 24 months at all sites in group A, B, C, and a decrease at all sites in group D ; there were heterogeneous results in groups (A, B, C), and D [Figure 2]. At 24 months, the bone mineral density of the greater trochanter increased significantly from base line in groups (A, B, C) (0.019 ± 0.005 g per square centimeter; P < 0.017), and the bone mineral density of Ward's triangle decreased significantly in group D (-0.020 ± 0.006 g per square centimeter; P < 0.017).
Figure 2: Mean (±SE) changes in bone mineral density of the greater trochanter (blue bars), Ward's Triangle (red bars), and the femoral neck (green bars) (as measured by dual-photon absorptiometry) after 24 months, in Group A (Alendronate), Group B (Ibandronate;), Group C (Zolidronic acid), and Group D (daily calcium and vitamin-D). The star indicates a signifi cant change from base line (P < 0.017)

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To determine whether the increase in the bone mineral density of the spine occurred at the expense of the bone mass of the hip, the change in spinal bone mineral density, expressed as the slope of the regression of the percentage change in bone mass plotted against time, was compared with the change in the bone mineral density of Ward's triangle, similarly expressed. Ward's triangle was chosen for this comparison because it was the site in the hip at which the greatest decrease in bone mineral density occurred. No correlations were found between the changes in bone mineral density at these two skeletal sites in any treatment group (data not shown).

Radiographic findings and new vertebral and non-vertebral fracture

There were few new vertebral fractures in the groups A, B, C (bisphosphonates) as compared to Group D (calcium and Vitamin D). About only three patients of total of combined group A, B, C were diagnosed with new vertebral fractures as compared to the group D in which 5 out of 16 were with new vertebral fractures. This when compared in percentage is almost more than double of groups using bisphosphonates.

The vertebral-fracture rate was reduced by two-thirds in the bisphosphonates-treated subgroups with low bone mineral density (42.3 fractures per 1,000 patient-years in the patients who received bisphosphonates as compared with 132.7 fractures per 1,000 patient-years in those who did not; P = 0.004) [Table 3]. The non-vertebral fractures that could be attributed to osteoporosis were distributed across treatment groups: Three hip fractures (one in group B and two in group A), two pelvic fractures (both in groups D), and four wrist fractures (two each in groups D and C).

Biochemical Analysis

Serum alkaline phosphatase levels declined steadily in bisphosphonate-treated groups throughout the study period; the mean level in group C (Zoledronic acid) was significantly lower at 24 months than at base line (69.3 ± 2.6 vs. 79.9 ± 3.6 U per liter; P < 0.0001). No other changes in biochemical variables were detected when base-line values were compared with those obtained at the end of the study. There were no significant differences in serum calcium, creatinine, or phosphorus levels, or urinary calcium: Creatinine or hydroxyproline: Creatinine ratios between treatment groups during the study.

Adverse effects on the jaw

To categorize 64 patients and to facilitate in study, the grading for changes in oral tissue was formulated.

Grade 0 - No significant change is seen in the oral health of patient (changes in CAL< 2 mm). Number of teeth same as before, no bone clinical evidence of necrotic bone or unhealed socket

Grade 1 - Individuals with two or less teeth lost during study or/and changes in CAL 2-4 mm and clinical evidence of exposed bone but without any infection (no acute pain or foul odour or puss discharge or necrotic bone seen clinically).

Grade 2 - Individuals with more than two teeth lost during the study or/and changes in CAL more than 4 mm and clinical evidence of exposed necrotic bone with infection (acute pain and/or foul odour seen clinically).

Grade 3 - All of grade 2 plus one or more of following: Pathological fracture, extra oral fistula or osteolysis extending to the inferior border of mandible or sinus floor (seen clinically and with relevant intra oral peri apical x-ray).

During the study, 10 cases out of 64 were having significant affects on jaws have been listed in [Table 4].
Table 4: Patients with significant effects on jaw seen during the study

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From [Table 3], it is clear that the cases that were clinically seen during the study of 2 years that bisphosphonates showed a significant effect on the healing of jaw bones, the results point out to that the long acting Zoledronic acid (IV) group (Group C) showed the majority of effects in comparison with Alendronate and Ibandronate (oral).

Statistically seeing at the end of study, Group C (zoledronic acid) had around 30% (5/16) of the patients affected with jaw disease as compared to Group A and B about 12% (4/32) and Group D showed negligible significance value. One patient in D group with unhealed socket can be attributed to other factors as this group was not exposed to bisphosphonates during the 2-year study.

Some of the percentage values in this study can be misleading because of the low sample size (64 patients) in the study. But the main aim was to show that there is relationship between the use of bisphosphonates and jaw healing. This is higher in case of intra-venous bisphosphonates as compared with oral bisphosphonates used. There were also seen changes in CAL in Group A, B, C patients as compared to Group D patients (data not shown here).


  Discussion Top


Clinical therapy with bisphosphonates for the osteoporotic patient, whether it was oral dosage of the alendronate (having a weekly action), Ibandronate (having monthly action), or IV administration of zoledronic acid (yearly action), resulted in significant increases in the bone mineral density of the spine after 12 months that were sustained for the remainder of the 24-month study period. There was significant (50%) decrease in the rate of new vertebral fractures in the combined bisphosphonate-treated groups as compared with the group that did not receive bisphosphonates. The increases in bone density and reduction in vertebral-fracture rates associated with all these bisphosphonates drugs treatment are most likely attributable to its anti-resorptive activity on the osteoclasts of the bone.

The effects of bisphosphonates on bone mass were most pronounced in the spine, a site rich in trabecular bone. The increase in spinal bone density did not occur as a result of losses of bone mass of the hip or wrist. The responses to treatment with bisphosphonates at other skeletal sites were heterogeneous. The failure of the hip and wrist to mirror the improvement in bone mass noted in the spine was not unexpected; previous studies of therapy of osteoporosis [11],[12] have shown varying responses at skeletal sites with different proportions of trabecular and cortical bone, indicating that the response to treatment is not uniform at different skeletal sites. [12]

There is an inverse relation between bone mineral density and the rate of vertebral fracture, [13],[14],[15],[16] which is confirmed in our study: The rate of new vertebral fractures was reduced by two-thirds in the subgroup with low bone mineral density that received bisphosphonate as compared with the subgroup that did not.

Also the study was done to see the comparison between the short acting and the long acting bisphosphonates. The short acting alendronate showed a non significant difference in mineralizing and antiresoptive properties as compared to long acting Ibandronate and zoledronic acid. Though it has been seen that the costs are less and the patient compliance was seen with the long acting ones. This suggests that bisphosphonates therapy provides the greatest protection against fracture in patients who have already had substantial losses in vertebral bone mineral density.

Rare cases of adverse effects of both long and short acting bisphosphonates on the jaw have been reported in the literature. These side-effects can be seen as drawback to the therapy. Our study with the help of dental professionals was able to show relationship between the long acting Zoledronic acid (IV) and the adverse osteonecrosis like symptoms of jaw which were less in case of oral short acting bisphosphonates and almost negligible in case of vitamin D and calcium therapies. It was also seen that these side effects could be kept under check on regular dental guidance and check-ups.

Whether the observed positive effects and the apparent adverse effects of bisphosphonate therapy would be maintained for more than two years is not known, hence this study is being extended to address this particular question. Other doses and schedules of bisphosphonate drugs may be equally or more effective than those we studied. It should be noted that oral Alendronate and Ibandronate are poorly absorbed; because food further decreases its absorption, so they must be taken on an empty stomach (1 hour before meals or 2 hours after). [17],[18] Failure to ensure that the drugs are taken in this manner may account for some of the negative results in studies using these drugs. [19]


  Conclusion Top


In this study, we found that bisphosphonate therapy was effective for osteoporosis. Two years of therapy resulted in significant increases in the bone mineral density of the spine and reductions in vertebral-fracture rates. These beneficial effects were greatest in the women who had the lowest spinal bone mineral densities at the beginning of the study. Side-effects on healing of the jaw bone was seen which was controllable under proper Dental professional observation. Oral Alendronate, Ibandronate and intra-venous/muscular zoledronic acid is simple to administer and compares favorably in cost to other treatments for osteoporosis (e.g., estrogen or calcitonin).

This study recommends that long term bisphosphonate therapy should be a welcome addition to the therapeutic options for osteoporosis, restoring bone mass and reducing the risk of vertebral fractures in patients with this debilitating disease and also it is recommended that patients should see their dentist before beginning oral or intravenous bisphosphonate therapy so that dental hygiene can be optimized. It is also recommended to dentists to take into consideration history of patient with the bisphosphonates while diagnosing and treatment planning.


  Acknowledgement Top


Mr. Gurmukh - Statistician.



 
  References Top

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Alldredge BK, Kimble K, Anne M, Lloyd Y, Kradjan WA, Guglielmo BJ. Applied therapeutics: The clinical use of drugs. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009. p. 101-3.  Back to cited text no. 1
    
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Guyatt GH, Cranney A, Griffith L, Walter S, Krolicki N, Favus M, et al. Summary of meta-analyses of therapies for postmenopausal osteoporosis and the relationship between bone density and fractures. Endocrinol Metab Clin North Am 2002;31:659-79.  Back to cited text no. 5
    
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Sambrook P, Cooper C. Osteoporosis. Lancet 2006;367:2010-8.  Back to cited text no. 6
    
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Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B; Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw-2009 update. Aust Endod J 2009;35:119-30.  Back to cited text no. 8
    
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NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785-95.  Back to cited text no. 9
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Migliorati CA, Schubert MM, Peterson DE, Seneda LM. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: An emerging oral complication of supportive cancer therapy. Cancer 2005;104:83-93.  Back to cited text no. 10
    
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Gruber HE, Ivey JL, Baylink DJ, Matthews M, Nelp WB, Sisom K, et al. Long-term calcitonin therapy in postmenopausal osteoporosis. Metabolism 1984;33:295-303.  Back to cited text no. 11
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Chesnut CH 3 rd , Ivey JL, Gruber HE, Matthews M, Nelp WB, Sisom K, et al. Stanozolol in postmenopausal osteoporosis: Therapeutic efficacy and possible mechanisms of action. Metabolism 1983;32:571-80.  Back to cited text no. 12
    
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Wasnich RD, Ross PD, MacLean CJ, Davis JW, Vogel JM. A prospective study of bone mass measurements and spine fracture incidence. In: Christiansen C, Johansen JS, Riis BJ, editors. Osteoporosis 1987: International Symposium on Osteoporosis. Copenhagen: Osteopress ApS, 1987. p. 377-8.  Back to cited text no. 14
    
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Fleisch H. Experimental basis for the use of bisphosphonates in Paget′s disease of bone. Clin Orthop 1987;217:72-8.  Back to cited text no. 17
    
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Fogelman I, Smith L, Mazess R, Wilson MA, Bevan JA. Absorption of oral diphosphonate in normal subjects. Clin Endocrinol (Oxf) 1986;24:57-62.  Back to cited text no. 18
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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