|Ahead of print publication
Bone Mineral Density is Decreased in Patients with Systemic Sclerosis and Correlates With Serum Intact Parathormone Levels: A Cross-Sectional Study
Shefali Sharma1, Aadhaar Dhooria1, Tulika Singh2, Varun Dhir1, Arghya Chattopadhyay1, Debashish Mishra1, Sanjay Jain1
1 Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Objective: To study bone mineral density (BMD) in Indian patients with systemic sclerosis and objectively verify whether an association exists between osteoporosis and systemic sclerosis.
Methods: Adult patients suffering from systemic sclerosis (as per the 2013 American College of Rheumatology classification criteria for systemic sclerosis) attending the rheumatology clinic at Post Graduate Institute of Medical Education and Research, Chandigarh, India were recruited. BMD was measured using dual energy x-ray absorptiometry (DXA) and serum Vitamin D and iPTH levels were estimated. The 10-year probability of sustaining an osteoporotic fracture was estimated using the World Health Organisation fracture risk assessment tool with the Indian population reference.
Results: 100 patients were included (89 women). Interstitial lung disease and pulmonary arterial hypertension were seen in 48 and 18 patients, respectively. Median (range) serum 25 hydroxy Vitamin D level was 17 ng/ml (3.7-225.7 ng/ml). Mean serum iPTH level was 79.6±38.1 pg/ml. 55 patients were categorized as Vitamin D deficient, 24 as insufficient, and 21 as Vitamin D sufficient. 21 patients had iPTH values above 75 pg/ml. 28% had osteoporosis of the lumbar spine while 6% had osteoporosis of the femoral neck. Serum iPTH correlated inversely with low bone mass at the hip (P = 0.023, r2 = 0.121). Low bone mass did not correlate with age, postmenopausal status, low BMI, corticosteroid use, serum 25 hydroxy Vitamin D levels, disease duration, presence of interstitial lung disease or pulmonary arterial hypertension.
Conclusion: Low bone mass is highly prevalent in patients with systemic sclerosis and is associated with elevated serum iPTH levels.
Keywords: Bone mineral density, osteoporosis, systemic sclerosis
|How to cite this URL:|
Sharma S, Dhooria A, Singh T, Dhir V, Chattopadhyay A, Mishra D, Jain S. Bone Mineral Density is Decreased in Patients with Systemic Sclerosis and Correlates With Serum Intact Parathormone Levels: A Cross-Sectional Study. Indian J Rheumatol [Epub ahead of print] [cited 2019 May 25]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=256778
| Introduction|| |
Osteoporosis (OP) is characterized by low bone mass and loss of normal architecture of the bones. Patients with OP have a high risk of fractures, especially of the hip and vertebrae, and this results in an increased morbidity and mortality. Some of the important factors increasing the risk of OP include age, family history, corticosteroid use, smoking and excessive alcohol use, and disorders interfering with intestinal absorption or metabolism of Vitamin D. It is a common observation that many patients with chronic inflammatory diseases have an increased risk of OP and fracture, which are usually brought about by prolonged corticosteroid therapy.
Systemic sclerosis (SSc) is a systemic autoimmune disease which is associated with vascular, immune, and fibrotic changes in the skin and some internal organs. SSc patients have many risk factors pointing toward the development of OP in them, including SSc being a chronic inflammatory state, occult malabsorption, malnutrition, immobilization, and use of corticosteroid therapy. However, results elaborating the association between SSc and OP have been conflicting,,,, Therefore, we aimed to investigate the bone mineral density (BMD) status in Indian SSc patients.
| Patients and Methods|| |
This was a cross-sectional study where we recruited consenting adult patients suffering from SSc (as per the 2013 American College of Rheumatology classification criteria for SSc) attending the rheumatology clinic at Post Graduate Institute of Medical Education and Research, Chandigarh, India, from January 2014 to December 2014, after obtaining Institutional Ethics Committee (IEC number: NK/1256, Dated 5.12.2013) clearance to the protocol. Patients with advanced renal failure and patients on bisphosphonates were excluded from the study. In addition to demographic details, we performed a routine physical examination and collected laboratory data including serum levels of calcium, phosphorous, vitamin D, and intact parathormone (iPTH). Patients were classified as Vitamin D deficient (25[OH]D below 20 ng/ml [50 nmol/L]), insufficient (25[OH]D of 21–29 ng/ml [52.5–72.5 nmol/L]), and sufficient (25[OH]D above 30 ng/ml [75 nmol/L]) based on the US Endocrine Society cutoffs. We also collected details regarding previous glucocorticoid and cyclophosphamide therapy.
DXA (dual energy X-ray absorptiometry) scan was performed using Hologic viewer 6.0 (Model-Discovery A [S/N 87292]) at lumbar spine and left femoral neck, and T scores and Z scores were calculated as per manufacturer's data. Patients with BMD T score ≤−1.00 were classified as “Low bone mass,” and those with BMD T scores >−1.00 as “Normal bone mass.” OP was defined as a T score below −2.5 SD and osteopenia was defined as a T score between −1.0 SD and −2.5 SD below the young adult mean (WHO standards).
The online FRAX® calculator was used to calculate the 10-year probability of suffering from a major osteoporotic fracture and hip fracture using the Indian population reference. BMD was entered as the T score.
Data were entered into MS Excel© 2007 and analyzed using SPSS version 20 software. Normality of data was checked using Shapiro–Wilk test. Data were expressed as mean ± standard deviation for normative data and median (range) for nonnormally distributed data. Student's t-test was used for comparison between means, Chi-square test for categorical variables and Mann–Whitney U test for medians. Correlations were estimated using Pearson correlation. Linear regression analysis was used for predictor variables. P < 0.05 was considered statistically significant.
| Results|| |
A total of 100 patients were recruited over a period of 1 year; 89 were women. Median disease duration was 5 years (1–30 years). Comorbidities in the patients include dermatomyositis overlap (1 patient), interstitial lung disease (ILD) (48 patients), and pulmonary arterial hypertension (PAH) (18 patients). Fifty-six patients (56%) received treatment with corticosteroids ever; most of these received 7.5 mg/d of corticosteroids initially, and the dose was tapered to 5 mg once a day and then to alternate days and subsequently was stopped. Sixteen patients had received cyclophosphamide for interstitial lung disease, and all had received it as a monthly pulse for 6 months [Table 1].
Low levels of calcium and phosphorus were found in 41 and 25 patients, respectively. Steroid use (P = 0.723), cyclophosphamide use (P = 0.359), sex (P = 0.145), presence of ILD (P = 0.987), or PAH (P = 0.739) did not vary significantly between the groups (on the basis of calcium levels). Median levels of 25(OH) Vitamin D were 17 ng/ml (3.7–225.7 ng/ml). According to the US Endocrine Society cutoffs, the number of patients categorized as deficient, insufficient, and sufficient Vitamin D were 55, 24, and 21, respectively. Mean levels of serum iPTH levels was 79.6 ± 38.1 pg/ml, and 21 patients had iPTH values above 75 pg/ml. Serum iPTH levels did not correlated with serum 25(OH) vitamin D levels (P = 0.104), serum calcium (P = 0.071), or serum phosphorus (P = 0.121). Serum 25(OH) vitamin D levels also did not correlate with serum calcium (P = 0.521) or serum phosphorus (P = 0.909).
Osteopenia and OP were seen in 44 and 28 patients at the lumbar spine, respectively and in 36 and 6 patients at the femoral neck, respectively. It was observed that patients with low bone mass, in comparison with those with normal bone mass in the femoral neck (and not in lumbar spine) had statistically significant higher values of serum iPTH (80.76 vs. 71.54 pg/ml; P = 0.048). All other variables did not significantly differ between patients having normal and low bone mass in lumbar spine as well as in femoral neck [Table 2]. The prevalence of low bone mass at the hip as well as spine did not differ among ever corticosteroid users and never corticosteroid users (P = 0.065, P = 0.76, respectively).
FRAX® scores were calculated for 55 eligible patients (over the age of 40 years). The median 10 years' probability for a fracture was 1.7% for a major osteoporotic fracture and 0.2% for a hip fracture. The maximum probability for a major osteoporotic fracture was 22% and for a hip fracture was 15%. A linear regression model built using BMI, postmenopausal status, steroid and cyclophosphamide use, ILD, PAH, and serum iPTH showed that only serum iPTH was negatively associated with low bone mass at the femoral neck (r2 = 0.121, P = 0.023).
| Discussion|| |
Our study documents the objective association of SSc and markers of OP in Indian patients. The patient population was diverse with a sex ratio of 8:1 (Female: Male) as would be expected of a population with SSc.
A significant proportion of patients was found to have hypocalcemia and hyperphosphatemia in our study. Steroid use was not associated with the presence of hypocalcemia in our patients. This may reflect the poor nutritional status in patients with SSc, which has been variously ascribed to factors such as poor mobility, bacterial overgrowth, and feeding difficulties.
Vitamin D deficiency is a burgeoning problem in India. The prevalence of Vitamin D deficiency is believed to be over 90% in some studies. Mean Vitamin D levels as low as 7.8 ng/ml have been reported in Indian physicians and nurses. We also found that as many as 79% of our patients had Vitamin D deficiency with a median value of 17 ng/ml. Twenty-one patients had an elevated serum iPTH levels, this may be a physiological response to Vitamin D deficiency as well as the consequent hypocalcemia even though a statistically significant correlation was not seen between these variables. Braun-Moscovici et al. also found elevated iPTH levels in 21.7% of their patients. They also postulated that the elevated iPTH levels may play a role in the development of acro-osteolysis.
OP was common in our patients seen in 28 at the Lumbar spine and 6 at the femoral neck. Serum iPTH levels were higher in patients with low bone mass at the hip as compared to those with high bone mass (89.3 ± 42.1 pg/ml vs. 72.6 ± 33.7, P = 0.03). Caimmi et al. did not find any correlation between lumbar spine Z scores and PTH levels. We did not find any association between low bone mass and traditional risk factors such as increasing age,,, postmenopausal status,, low BMI,,,, corticosteroid use, serum 25 (OH) Vitamin D levels, or with disease specific factors such as disease duration and presence of ILD or PAH.
OP in rheumatic diseases is a common morbidity. While corticosteroid use is well known to contribute to OP, chronic inflammation is also believed to play a major role. In patients with rheumatoid arthritis, TNF-α, IL-1, IL-6, and IL-17 have all been implicated in increased osteoclastogenesis., Additive risk factors believed to contribute towards OP in SSc patients include calcinosis, acroosteolysis, and disease duration. Our study further confirms the presence of low bone mass in these patients.
The major limitation of our study is the poor sample size; further studies with higher samples are required to validate our results. Further, most of our patients were relatively young and had the disease for a relatively shorter duration as compared to similar studies reported in the past.,,,, Finally, we did not include non-disease controls in our study.
To conclude, we have shown that low bone mass is common in patients with SSc and is associated with elevated serum iPTH levels. Hypocalcemia is also highly prevalent in these patients and deserves treatment to prevent untoward long-term effects on bone metabolism and quality of life.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
La Montagna G, Baruffo A, Abbadessa S, Maja L, Tirri R. Evidence for bone resorption in systemic sclerosis. J Rheumatol 1995;22:797-9.
Loucks J, Pope JE. Osteoporosis in scleroderma. Semin Arthritis Rheum 2005;34:678-82.
Yuen SY, Rochwerg B, Ouimet J, Pope JE. Patients with scleroderma may have increased risk of osteoporosis. A comparison to rheumatoid arthritis and noninflammatory musculoskeletal conditions. J Rheumatol 2008;35:1073-8.
Avouac J, Koumakis E, Toth E, Meunier M, Maury E, Kahan A, et al.
Increased risk of osteoporosis and fracture in women with systemic sclerosis: A comparative study with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012;64:1871-8.
Allanore Y, Avouac J, Wipff J, Kahan A. New therapeutic strategies in the management of systemic sclerosis. Expert Opin Pharmacother 2007;8:607-15.
Souza RB, Borges CT, Takayama L, Aldrighi JM, Pereira RM. Systemic sclerosis and bone loss: The role of the disease and body composition. Scand J Rheumatol 2006;35:384-7.
Sampaio-Barros PD, Costa-Paiva L, Filardi S, Sachetto Z, Samara AM, Marques-Neto JF, et al.
Prognostic factors of low bone mineral density in systemic sclerosis. Clin Exp Rheumatol 2005;23:180-4.
Frediani B, Baldi F, Falsetti P, Acciai C, Filippou G, Spreafico A, et al.
Clinical determinants of bone mass and bone ultrasonometry in patients with systemic sclerosis. Clin Exp Rheumatol 2004;22:313-8.
Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int 2008;19:385-97.
Goswami R, Gupta N, Goswami D, Marwaha RK, Tandon N, Kochupillai N, et al.
Prevalence and significance of low 25-hydroxyvitamin D concentrations in healthy subjects in Delhi. Am J Clin Nutr 2000;72:472-5.
Braun-Moscovici Y, Furst DE, Markovits D, Rozin A, Clements PJ, Nahir AM, et al.
Vitamin D, parathyroid hormone, and acroosteolysis in systemic sclerosis. J Rheumatol 2008;35:2201-5.
Caimmi C, Caramaschi P, Barausse G, Orsolini G, Idolazzi L, Gatti D, et al.
Bone metabolism in a large cohort of patients with systemic sclerosis. Calcif Tissue Int 2016;99:23-9.
Mok CC, Chan PT, Chan KL, Ma KM. Prevalence and risk factors of low bone mineral density in Chinese patients with systemic sclerosis: A case-control study. Rheumatology (Oxford) 2013;52:296-303.
Marot M, Valéry A, Esteve E, Bens G, Müller A, Rist S, et al.
Prevalence and predictive factors of osteoporosis in systemic sclerosis patients: A case-control study. Oncotarget 2015;6:14865-73.
Omair MA, McDonald-Blumer H, Johnson SR. Bone disease in systemic sclerosis: Outcomes and associations. Clin Exp Rheumatol 2014;32:S-28-32.
Koumakis E, Avouac J, Winzenrieth R, Toth E, Payet J, Kahan A, et al.
Trabecular bone score in female patients with systemic sclerosis: Comparison with rheumatoid arthritis and influence of glucocorticoid exposure. J Rheumatol 2015;42:228-35.
Atteritano M, Sorbara S, Bagnato G, Miceli G, Sangari D, Morgante S, et al.
Bone mineral density, bone turnover markers and fractures in patients with systemic sclerosis: A case control study. PLoS One 2013;8:e66991.
Ibn Yacoub Y, Amine B, Laatiris A, Wafki F, Znat F, Hajjaj-Hassouni N, et al.
Bone density in moroccan women with systemic scleroderma and its relationships with disease-related parameters and Vitamin D status. Rheumatol Int 2012;32:3143-8.
Maruotti N, Corrado A, Cantatore FP. Osteoporosis and rheumatic diseases. Reumatismo 2014;66:125-35.
Takayanagi H. Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol 2009;5:667-76.
[Table 1], [Table 2]