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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 15  |  Issue : 1  |  Page : 32-38

Acro-osteolysis and its relationship with bone mineral density and peripheral vascularity in premenopausal females with systemic sclerosis


1 Department of Rheumatology and Rehabilitation, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Rheumatology and Rehabilitation, Faculty of Medicine, Zagazig University, Zagazig, Egypt; Department of Physical Medicine and Rehabilitation, Dubai Hospital, Dubai, UAE
3 Department of Radio-Diagnosis, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Web Publication30-Mar-2020

Correspondence Address:
Dr. Sahar S Khalil
Department of Physical Medicine and Rehabilitation, Dubai Hospital, P. O. 7272, Al-Baraha Area, Dubai

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_144_19

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  Abstract 


Objectives: To investigate the relationship between acro-osteolysis (AO), bone mineral density (BMD) and peripheral vascularity in premenopausal female patients with diffuse systemic sclerosis (dcSSc).
Methods: An observational cohort study that included thirty premenopausal female patients with dcSSc. The recruited patients were categorized into two groups according to the presence of radiological signs of AO. Patients were assessed clinically, laboratory and radiologically by X-ray imaging of both hands and wrists, dual-energy X-ray absorptiometry for measuring BMD and Doppler ultrasonography for evaluation of upper limbs peripheral vascularity.
Results: Overall, 80% patients had AO; comparing patients with and without AO, the former had significant increase in the frequencies of Raynaud's phenomenon, calcinosis and digital pits (88.5, 94.7, 91.7) versus (11.5, 5.3, 8.3) in the latter, respectively. Additionally, they had significantly lower distal radius BMD and higher macrovascular abnormalities at both radial and ulnar arteries ( P < 0.05). On regression analysis, the most important factors associated with AO were calcinosis (OR= 1.7; 95% CI: 1.01- 3.02; P = 0.02), Raynaud's phenomenon (OR= 3.5; 95% CI: 0.6-19.4; P = 0.003), digital pits (OR= 2.8; 95% CI: 0.9-8.8; P = 0.001), low BMD at the distal radius (OR= 1.9; 95% CI: 1.1-3.0; P = 0.002), and macrovascular changes at radial and ulnar arteries (OR = 2.2; 95% CI: 0.7-6.5; P = 0.04 and OR =1.6; 95% CI: 0.9-3.0; P = 0.05) respectively.
Conclusion: Calcinosis, Raynaud's phenomenon, digital pits, vascular alterations at radial and ulnar arteries, and low BMD at the distal radius are the most important factors associated with AO in dcSSc patients.

Keywords: Acro-osteolysis, bone mineral density, systemic sclerosis, vascular changes


How to cite this article:
Zaghlol RS, Khalil SS, Almolla RM, El-Maghraby AM, Makarm WK. Acro-osteolysis and its relationship with bone mineral density and peripheral vascularity in premenopausal females with systemic sclerosis. Indian J Rheumatol 2020;15:32-8

How to cite this URL:
Zaghlol RS, Khalil SS, Almolla RM, El-Maghraby AM, Makarm WK. Acro-osteolysis and its relationship with bone mineral density and peripheral vascularity in premenopausal females with systemic sclerosis. Indian J Rheumatol [serial online] 2020 [cited 2021 Oct 16];15:32-8. Available from: https://www.indianjrheumatol.com/text.asp?2020/15/1/32/278883




  Introduction Top


Systemic sclerosis (SSc) is a connective tissue disease characterized by immunological disturbances, microangiopathy, and excessive fibrosis of the skin, internal organs, and vessels.[1] It is a relatively rare disease with an incidence ranging from 2 to 20 cases per million people.[2]

The vascular impairment in SSc patients is assumed to be the primary pathological process which is mediated by autoimmunity and results in tissue fibrosis.[3] In addition, it has also been reported that the presence of several anti-angiogenic factors in patients with SSc could be an important factor in the vascular regeneration abnormalities and angiogenesis insufficiency found in this disease.[4],[5]

Acro-osteolysis (AO), which means the resorption of digital terminal tufts, is one of the musculoskeletal manifestations of SSc, which is associated with pain and disability.[6],[7] It is very suggestive of SSc, though not pathognomonic, being encountered in some other diseases.[8],[9],[10],[11]

The etiopathogenesis of AO in SSc is poorly understood; several theories have been proposed including primarily; the impairment of the digital vascular supply due to occlusive vasculopathy, external compression by the tightened skin, impaired angiogenesis following hand microtrauma, neural impairment due to compression neuropathy, and finally, the possible association of occult hyperparathyroidism secondary to Vitamin D deficiency.[9],[10],[11]

Nevertheless, the main mechanism for AO is mostly the vascular impairment, which leads to the disturbance in bone homeostasis in favors of bone resorption and enhanced osteoclastogenesis.[12] Tissue hypoxia in normal situations stimulates angiogenesis; conversely, SSc characterized by an inefficient angiogenesis and replacement of the damaged blood vessels.[13]

Very little is known about bone mass in the SSc, and there are conflicting data regarding the presence or absence of osteoporosis (OP).[14],[15] However, several studies have reported lower peripheral and axial bone density and increased risk of OP in patients with SSc.[16],[17],[18]

Taking into consideration, all the previous findings had led us to hypothesize that similar enhanced osteoclastogenesis triggered by local hypoxia, may also lead to the development of both local OP and AO in SSc patients. Hence, the present study aimed to investigate the relationships between AO, bone mineral density (BMD), and peripheral vascular status in premenopausal women with SSc.


  Methods Top


Study population

This study is a single-center observational cohort study that included 30 consecutive female patients with diffuse systemic sclerosis (dcSSc) recruited from the outpatient clinics of the rheumatology and rehabilitation department of a big tertiary hospital. The study was carried out from May 2018 to May 2019. The study was approved by the Local Ethical Committee of the university, and it was designed following the Declaration of Helsinki. Written informed consent was obtained from each patient before entering the study.

The patients were included if they were adult premenopausal females who diagnosed with dcSSc based on the criteria of the American College of Rheumatology/European League Against Rheumatism.[19]

The exclusion criteria were menopausal women, presence of any bone demineralizing diseases, chronic diseases such as renal failure or chronic respiratory failure, cardiovascular risk (poorly controlled elevated blood pressure, diabetes, and dyslipidemia), other coexisting chronic inflammatory rheumatic diseases, prior or family history of previous pathology fracture, history of using of Vitamin D or calcium supplements or treatment with anti-OP medications within the past year, and current or past history of smoking and alcohol intake.

Data were collected on demographic and disease parameters including age, weight, height, clinical characteristics (disease duration, disease subtype as defined by LeRoy et al.,[20] Raynaud's phenomenon [RP], skin manifestation, acral and joints involvement, calcinosis and internal organ involvement, and current treatments). Calcinosis was diagnosed by evidence of calcium deposits on physical examination and/or radiography of the extremities, abdomen, chest wall, and the trunk and/or a clear history of calcium extrusion from the skin as described by the patient. The skin involvement was assessed by the modified Rodnan skin thickness score.[21] Laboratory investigations included the assessment of serum levels of autoantibodies such as antinuclear antibody and anti-scleroderma 70 (anti-scl-70), calcium, 25-hydroxyvitamin D, and parathyroid hormone (PTH).

The recruited 30 patients were further categorized into two groups according to the presence of radiologic AO as the following: Group I included patients with radiologic AO (n = 24) and Group II included patients without AO (n = 6).

Imaging studies

Radiographic X-ray imaging

A standard anterior-posterior (AP) view of X-ray both hands was obtained for each patient and evaluated for the presence of both AO and calcinosis. Then, for the detected AO, it was graded according to the scoring scale system developed by Johnstone et al.,[22] as follows:

”(0) normal terminal phalanges, no resorption (1), minimal AO, small amount of resorption at the terminal tuft, (2) resorption of most of the distal tip of the terminal tuft, (3) resorption of most of the terminal tuft, leaving only one side intact, and (4) complete resorption of the terminal tuft, with obvious penciling.” Then, the overall grading of (normal/minimal, moderate, or severe AO) was described in each patient according to the following: ”(0) normal/minimal AO: Maximum score for an individual finger = 1 and total score (sum of all fingers) ≤8, (1) moderate AO: Maximum score for an individual finger ≤2 and total score from 9 to 16 inclusive, and (2) severe AO: Maximum score for an individual finger ≥3 or total score ≥17” [Figure 1]a and [Figure 1]b.
Figure 1: (a) X-ray radiography of both hands (anterior-posterior) showing severe acro-osteolysis (ranging from penciling, complete resorptions of the terminal tufts). (b) X-ray radiography of both hands (anterior-posterior) showing mild acro-osteolysis (terminal tufts erosive changes in second and third digits in the left hand and first and second digits in the right hand). (c) Duplex ultrasound showing left ulnar artery reduction in flow velocity more than 50% than that in the left brachial artery (52.4 cm/s). (d) Duplex ultrasound showing left ulnar artery reduction in flow velocity more than 50% than that in the left brachial artery (59.4 cm/s)

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Bone mineral density (BMD) assessment

BMD (g/cm2) was quantified by dual-energy X-ray absorptiometry (DXA) using a Lunar Prodigy machine (GE Medical Systems, Madison, WI, USA). It was measured at the lumbar spine (L1-L4, anterior projection), femoral neck, and the distal end of the radius. Moreover, Z-score (standard deviations (SD) from the average BMD of age, sex, and ethnicity) and T-score (SD from peak bone mass) were calculated. OP was defined according to the World Health Organization criteria; patients were divided into three groups according to the BMD findings: patients with normal BMD (T-score >−1), patients with osteopenia (T-score between −1 and −2.5), and patients with OP (T-score <−2.5).[23]

Doppler ultrasound assessment

A comprehensive upper extremity arterial Doppler ultrasound (DUS) examination was performed for all included patients to assess the presence of any vascular abnormalities. The participants were scheduled at the same time of the day every morning ( first two or three patients) waited for at least 45 min in a room that was 24°C before being examined by DUS. Care was taken not to apply any pressure during the Doppler study using a large amount of gel over the examined vessel. The machine used was (Siemens Acuson X300 USG, linear probe frequency range: 5–10 MHz). Power Doppler settings were standardized (Doppler frequency: 8 MHz; velocity: 5 cm/s). The assessment included brachial, ulnar, and radial arteries of both sides. The peak systolic velocity in each vessel was assessed and reduction in velocity to ≤50% in the radial or ulnar arteries at the wrist compared to that in the brachial artery was considered as a positive sign for vasculopathy; while absent flow denoted vessel occlusion [Figure 1]c and [Figure 1]d.

Statistical analysis

The collected data were coded, entered, and analyzed using the Statistical Package for Social Science program (version 20, SPSS Inc., Chicago, IL, USA). Quantitative variables were expressed as mean ± SD if the data were normally distributed or median if the data were not. The qualitative variables were expressed as a number (n) and percentage (%). For quantitative variables analysis, independent samples t-test was used for normally distributed data, while for nonparametric data, the Mann–Whitney U-test was used. Fisher's exact test was used to detect the relation between different qualitative variables. Multivariate analysis was performed to detect the most powerful determinants of AO among SSc patients. The results were considered statistically significant when the significant P < 0.05.


  Results Top


Thirty female dcSSc patients (24 with AO and 6 without AO, mean age 33.77 ± 4.8 years and disease duration 8.6 ± 5.34 years) were included. No significant difference was found between patients with AO (Group I) and those without AO (Group II) in the demographic characteristics, received medications, or laboratory investigations. Regarding clinical manifestations, there was a significant increase in the frequency of RP, calcinosis and digital pits in Group I compared to Group II. Moreover, patients with AO had significantly low radial BMD, T- and Z-scores than those without AO, while no significant differences among both groups in femoral and lumbar BMD [Table 1].
Table 1: Demographic, laboratory, and clinical characteristics of enrolled patients

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The frequencies of radial and ulnar arteries involvement on DUS examination in the recruited patients were 83.3% and 70%, respectively. DcSSc patients with AO had significantly higher radial and ulnar arteries involvements on DUS examination compared to those without (P< 0.05) [Table 2]. However, further studying the relationship between this macrovascular and severity of AO, no significant differences were found between patients with moderate and severe AO (P > 0.05) [Table 3].
Table 2: Radial and ulnar arteries macrovasculature changes in patients with and without AO

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Table 3: Relation between macrovascular impairment and severity of acro-osteolysis (n=24)

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Regarding the relation between BMD level and AO severity, it was found that patients with severe AO (n = 12) had significantly lower distal radius BMD compared to those with moderate AO (n = 12) (P< 0.05). However, no significant difference was observed between them in lumbar or femoral BMD [Table 4].
Table 4: Relation between bone mineral density and severity of acro-osteolysis

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Multivariate regression analysis revealed that calcinosis, RP, digital pits, low BMD at the distal radius, and macrovascular changes in both radial and ulnar arteries were independent risk factors for AO (P< 0.05) [Table 5].
Table 5: Factors associated with acro-osteolysis on multivariate regression analysis

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  Discussion Top


The aim of this study was to investigate the relationship between AO, BMD, and peripheral vascularity in premenopausal female patients with dcSSc. AO of the terminal digital tufts is a well-known, but improperly addressed clinical feature of SSc. The exact mechanism that disturbs the local balance between bone formation and resorption is still uncertain.

In the present study, the frequency of AO was 80% of the enrolled dcSSc patients; the prevalence of AO varied greatly among different populations.[22],[24],[25],[26]

SSc patients with AO had higher frequencies of RP, calcinosis, and digital pits in comparison to those without AO; this matched the findings of many other previous studies.[6],[22],[27],[28]

In the present study, although digital ulcers were higher in SSc patients with AO compared to those without; contrary to expectations, the difference was not statistically significant (P = 0.17). This is consistent with a previously published study.[28] In contrast, another study reported a strong association between AO and digital ischemia.[22] The most likely explanation of this lack of association between AO and digital ulcers in the present study can be attributed to the use of vasodilator therapy and/or to the smaller number of recruited patients.

In the present study, there was a significant association between AO and vascular changes in radial and ulnar arteries. Several publications have suggested the strong relationship between hypoxia and vascular insufficiency with the development of AO.[11],[29],[30]

Another important finding in this study is the significantly lower BMD at the distal radius in patients with AO compared to those without; moreover, this reduced BMD was related to the severity of AO. Of note, there was no significant difference between patients with or without AO in the serum levels of Vitamin D, calcium, and PTH; moreover, generally, the patients had Vitamin D deficiency with normal parathyroid and serum calcium levels.

The association of SSc with low BMD, abnormal bone metabolism and/or OP has been discussed in several previous studies.[16],[31],[32] Furthermore, in a recent cross-sectional study on SSc patients, a strong association was found between low BMD and high serum level of intact PTH.[18]

In addition, in agreement with this study, another Egyptian study had investigated BMD in patients with SSc hand involvement compared to normal population; they found that SSc patients had a higher frequency of OP at the distal radius; moreover, those SSc patients with distal radius OP had significantly higher severity of hand involvement.[33]

Similarly, a retrospective cohort study of 5218 patients with SSc concluded that patients with AO are more likely to have calcinosis and OP than patients without AO; they speculated that a similar hypoxia-induced process that caused OP might also trigger the development of AO and calcinosis.[34]

As far as we know, no previous studies have investigated the BMD measured by DXA in SSc patients with AO; however, a recent study reported that SSc female patients have lower volumetric BMD and impaired bone microarchitecture at the distal radius detected by high-resolution quantitative computed tomography (HR-pQCT). In addition, this altered radial microarchitecture was significantly associated with micro- and macro-vascular affection.[35]

Furthermore, other reports have shown that selective bone loss at the radius cortical density measured by HR-pQCT was observed in patients with ischemic heart and peripheral vascular diseases.[36],[37] In addition, this localized reduction of BMD could be ischemia-related; as it leads to local hypoxia, pH changes, and disturbance of vascular permeability which may, in turn, affect the hematopoietic stem cells by inducing osteoblast apoptosis and impairing osteoblast function, leading to reduced bone formation and thus affecting the bone mass and density.[38],[39]

Hence, the key new findings in the present study are the lower distal radius BMD and higher frequencies of vascular insufficiency at radial and ulnar arteries in dcSSc patients with AO. In addition, we found that calcinosis, lower distal radius BMD, macrovascular impairment of radial and ulnar arteries are the most important risk factors associated with AO.

To the best of our knowledge, this is the first study to explore the relationships between AO severity, BMD, and vascular impairment in dcSSc patients. However, another study found a positive correlation between AO severity and increased osteoclast formation and higher vascular endothelial growth factor level in SSc patients. Increasingly, they suggested that using anti-resorption therapy that specifically targets osteoclast maturation and function, solely or in combination with vasodilators, might be a successful method to control AO, recover hypoxia, and impede osteoclastogenesis in SSc.[28]

The key limitation in this study is the relatively small number of recruited population, which is attributed to the meticulous selection criteria (to avoid bias due to other dependent risk factors) and the relative rarity of the disease. Further studies are required in this field to expand the information regarding AO development to develop a specified therapeutic option that helps in reducing its occurrence in SSc patients.


  Conclusion Top


The main factors associated with AO in the recruited dcSSc patients were calcinosis, RP, digital pits, vascular alterations at radial and ulnar arteries, and lower BMD at the distal radius. It would be of interest to meticulously investigate the association between AO, OP, and vasculopathy in an attempt to clarify the exact pathogenesis and guide the development of future specific therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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