1. Introduction

Patients with systemic sclerosis (SSc, scleroderma) are reported to have a significant reduction in bone mass with an increased risk of vertebral fracture, especially with a longer disease duration [1, 2]. One meta-analysis published in 2020 evaluated 18 studies using pooled weighted mean difference (WMD) to estimate the mean difference in BMD between patients with SSc and controls showed that patients with SSc had significantly lower bone mineral density (BMD) than controls in the following categories: whole body (WMD − 0.07, 95% CI − 0.1 to − 0.04, p < 0.00001), lumbar spine (WMD − 0.08, 95% CI − 0.11 to − 0.05, p < 0.00001), femoral neck (WMD: −0.28, 95% CI: −0.46 to −0.10, p = 0.002), total hip (WMD − 0.10, 95% CI − 0.14 to − 0.06, p < 0.00001), and femoral trochanter (WMD − 0.06, 95% CI − 0.09 to − 0.03, p < 0.0001) [1]. While this meta-analysis did not find a significant difference in the risk of osteoporotic fracture between patients with SSc and controls (OR = 2.24, 95% CI 0.58 to 8.59, p = 0.24), the patients with SSc had an increased risk of vertebral fracture (OR 10.38, 95% CI 1.19 to 90.58, p = 0.03) [1]. In a subsequent meta-analysis, the pooled prevalence of osteoporosis in patients with SSc was 27% (95% CI, 24–31), with moderate heterogeneity (I² = 61.6%) [2]. Meta-regression analysis was conducted to explore the sources of heterogeneity. This analysis of 22 studies identified significant risk factors for osteoporosis in SSc patients were age > 50 years (OR = 2.94, 95% CI, 1.52–5.68), menopause (OR = 3.90; 95% CI, 1.94–7.84), aging (MD = 8.40; 95% CI,6.10–10.71) and longer disease duration (MD = 4.78; 95% CI,1.83–7.73). However, female (OR = 1.45; 95% CI, 0.75–2.77), pulmonary arterial hypertension (OR = 0.50; 95% CI, 0.17–1.54), and diffuse cutaneous SSc (OR = 1.05; 95% CI, 0.75–1.48) were not significant risk factors for osteoporosis in SSc patients [2]. This data suggests osteoporosis is highly prevalent in patients with SSc, and similar in many countries, however a consensus approach on treatment of SSc osteoporosis is lacking. While these studies assessing epidemiology of osteoporosis in SSc are important, longitudinal data on treatment are lacking.

Early monitoring of bone mineral density in patients with SSc is recommended for the prevention of osteoporosis and fracture. However, treatment of low bone mineral density once detected can be a challenge to the treating physician. While treatment courses and monitoring of therapies are not within the scope of this review, SSc disease features such as intestinal malabsorption, patulous esophagus, and calcinosis are discussed as important considerations for bone health management in SSc patients.

2. Bone health screening

A bone health history must include consideration of age, sex, low body mass index, previous fragility fracture, parental history of hip fracture, glucocorticoid (GC) treatment, current smoking, and alcohol intake of 3 or more units daily to identify individuals at or above a ‘fracture threshold’ by the Fracture Risk Assessment Tool (FRAX). This fracture risk prediction tool was released in 2008 and provides country-specific algorithms to estimate the 10-year fracture risk using clinical and radiological data [3]. A dual energy X-ray absorptiometry (DXA) at the lumbar spine, total hip, and femoral neck for all patients is the gold standard for assessing bone mineral density (BMD) and is most often described as a T-score or Z-score, both of which are units of standard deviation (SD). The T-score describes the number of SDs by which the BMD in an individual differs from the mean value expected in young healthy individuals. The operational definition of osteoporosis is based on the T-score for BMD assessed at the femoral neck and is defined as a value for BMD 2.5 SD or more below the young female adult mean (T-score less than or equal to − 2.5 SD) [4]. Functional status and fall frequency are not accounted for in the FRAX and are important considerations in SSc.

The International Society for Clinical Densitometry (ISCD) provides official position statements on important topics in skeletal assessment, through a rigorous, validated method for recommendations that are not accounted for in the current version of FRAX [5]. The ISCD includes recommendations for lumbar spine, total hip and one-third (33%) radius T-scores [6] in certain circumstances, such as severe obesity or hyperparathyroidism in post-menopausal women. Expert opinion suggests bone densitometry using DXA may underestimate fracture risk in younger SSc patients. Trabecular bone score (TBS) and vertebral fracture assessments (VFA) are novel tools that may offer additional information to improve fracture prediction in chronic inflammatory disease, and may have applicability to SSc [7, 8, 9]. TBS is an adjunctive software application on DXA machines that performs novel gray-level texture measurements on lumbar spine DXA images, capturing information relating to trabecular microarchitecture [10]. While TBS values were similar in a small cohort of SSc patients, systematic coupling of VFA with BMD allowed the diagnosis previously unknown asymptomatic vertebral fractures [11]. Other imaging methods have been used in chronic inflammatory disease to assess bone deficits and independently predict fracture risk, such as quantitative ultrasound or peripheral quantitative computed tomography, however, these approaches are not currently accepted as routine screening tests [12].

There are no specific guidelines for DXA in SSc, however the recommendations for individuals with rheumatoid arthritis (RA), a more common rheumatic disease, can provide some guidance, with a recommendation to screen all patients over age 50 [12]. Both high daily and cumulative glucocorticoid (GC) doses increase risk of fracture, particularly vertebral fracture, due to the greater effects of GCs on trabecular bone than on cortical bone. Steroids should be avoided in SSc due to scleroderma renal crisis risk. However, if a SSc patient has inflammatory features requiring low-dose glucocorticoids, greater or equal to 2.5 mg per day for 3 months or longer, BMD screening age should include anyone 40 years and older [13]. Screening frequency should be based on ongoing risk factors. Based on RA literature, BMD screening in 3 to 5-year intervals for SSc who have normal BMD, well-controlled disease, and are not taking GCs could be considered. Whereas whole body bone, fat and lean mass can also be measured using DXA, these measurements do not assist in the routine diagnosis or assessment of osteoporosis [14].

3. Laboratory assessment

The initial basic bone health laboratory testing should consist of complete blood count (CBC), serum calcium, phosphorus, creatinine with estimated glomerular filtration rate (eGFR), 24 h urinary calcium and creatinine excretion panel, hepatic function tests (including a gamma-glutamyl transferase, if the alkaline phosphatase is elevated), thyroid stimulating hormone, parathyroid hormone, and serum 25-OH-D [12]. If a decreased serum albumin is detected in the screening assessment, additional studies can include serum protein electrophoresis, quantitative immunoglobulins with serum free light chains, and stool alpha-1 antitrypsin [12, 15]. If malabsorption is suspected, hydrogen breath testing can be useful for the diagnosis of small intestinal bacterial overgrowth (SIBO) as many patients with this complication may suffer from nutritional deficiencies and osteoporosis. However, SIBO testing may not be readily available outside of academic medical centers. If vitamins (B12, D, A, and E) as well as minerals (iron and calcium) deficiencies are detected, in addition to empiric treatment for SIBO, celiac screening should be considered [16, 17]. Independent of diarrhea, low vitamin D and calcium levels may reflect malabsorption and can be a risk factor for secondary hyperparathyroidism and bone resorption [18]. The importance of understanding the gastrointestinal tract involvement in SSc is critical to a bone health management for not only calcium and vitamin D replacement, but also phosphorus and magnesium supplementation [4]. In the setting of renal disease, phosphate-lowering therapies may be indicated. The response of secondary osteoporosis to conventional anti-osteoporosis therapy may be inadequate if the underlying condition is unrecognized and untreated [8].

3.1 Treatment of osteoporosis

Bone mass reduction in SSc occurs with traditional risk factures such as age and menopausal status, but due to gastrointestinal tract disease may have additional risk factors as identified by history or laboratory assessment (Figure 1). Therefore, in addition to risk factor modification, the treatment of osteoporosis must include assessment for calcium and vitamin D, and consideration of medication interventions (Table 1).

Figure 1.
Approach to bone health assessment in systemic sclerosis.

Medication Class	Important consideration of SSc disease features
Bisphosphonate	Consider if history of patulous esophagus, esophagitis, and reduced renal function.
Denosumab	Consider if history of erosive “RA-like” arthritis
Osteoanabolic	Consider if history of calcinosis
Hormone-based therapies	Consider if history of thrombosis

Table 1.

Medication class considerations.

3.2 Calcium and vitamin D

Confirmation of adequate calcium and vitamin D is an important step in osteoporosis management. Serum calcium levels are not an indication of nutritional calcium status. Validation of adequate calcium intake and absorption requires a 24-hour urine collection and analysis [19]. Laboratory “normal range reference intervals” for 24-hour calcium may vary by the race of the individual [20]. Recommendations should include a daily calcium intake of between 800 and 1200 mg and sufficient dietary protein, ideally achieved through dairy products [14]. Supplement use is recommended if adequate dietary intake is not achieved. Calcium supplement absorption and side effects may vary according to the calcium salt (e.g., calcium citrate vs. calcium carbonate or calcium formate). It is important to ask patients on calcium supplements about constipation, bloating, kidney stones, and possible vascular disease, which though not proven, is certainly a consideration in SSc [21]. As such, a dietary source rather than pill supplementation of calcium is preferred [22]. Supplementation with calcium alone does not reduce fracture risk, and vitamin D supplementation, rather than calcium, though controversial, may reduce falls risk in the elderly when combined with other prevention approaches [14, 23, 24].

Vitamin D replacement, 400–1000 IU per day, is generally recommended in patients receiving bone protective therapy and is proposed to not only have a beneficial effect on bone health, but may have a positive effect on the immune system in autoimmune disease [25, 26]. Lower vitamin D levels are reported in SSc with diffuse cutaneous disease when compared to the limited cutaneous subset [27]. The correct threshold for vitamin D replacement is debated due to differences in prior study designs, analysis, and randomized controlled trials. However, in RA the recommendation is to achieve 25-OH vitamin D level greater than 25 ng/ml to prevent hypocalcemia, especially in patients with chronic kidney disease receiving potent anti-resorptive drugs [12].

Calcinosis in SSc is associated with acro-osteolysis, digital ulceration, and osteoporosis, suggesting a link to severe vasculopathy [12]. Dystrophic soft-tissue calcification occurs in damaged or devitalized tissues in the presence of normal calcium/phosphorus metabolism and normal serum calcium and phosphorus levels [28]. Soft-tissue mineralization is a tightly regulated process relying on the activity of systemic and tissue-specific inhibitors and promoters of calcium precipitation. In SSc, this process is thought to be related to vascular hypoxia and in myositis-overlap disease related to release of calcium from mitochondria in damaged muscle cells [29]. The primary mineral component of calcinosis is hydroxyapatite in systemic sclerosis and carbonate apatite in dermatomyositis [29]. There is no published evidence related to calcium supplements and SSc calcinosis. However, radiologic scoring of calcinosis cutis offers an opportunity to objectively correlate this skin complication to reduction in BMD [30, 31].

3.3 Bisphosphonates

Bisphosphonates act by inhibiting osteoclast differentiation from osteoclast precursors. The oral bisphosphonates (alendronate, risedronate, ibandronate) may be used as initial treatments in most cases of osteoporosis, but potential gastrointestinal adverse effects are important considerations in SSc patients. Oral bisphosphonates are associated with mild gastrointestinal disturbances, and alendronate and pamidronate are associated with esophagitis, which is a concern in SSc patients with a patulous esophagus. Intravenous zoledronic acid has the highest probability of causing nausea and is associated with fever and bone and muscle pain that ameliorates or disappears after subsequent courses [32]. Osteonecrosis of the jaw has been described as an adverse effect of bisphosphonates and may be related to the class of bisphosphonate, differences in potency, and route of administration [14]. However, this potential adverse effect is often of concern to SSc patients with microstomia, in which dental procedures are challenging [33]. Bisphosphonates may have beneficial effects in a subgroup of calcinosis cutis patients [34]. Treatments should be reviewed after 3–5 years treatment with bisphosphonate, since a longer duration of bisphosphonates beyond 5 years has been associated with the risk of atypical femoral fracture. Fracture risk should be reassessed after a new fracture, regardless of when it occurs, because the risk of new fractures increases in patients who stop treatment [14].

3.4 Denosumab

The monoclonal antibody Denosumab is an inhibitor of receptor activator of nuclear factor-kB ligand (RANKL), which is necessary for osteoclast activation and survival. Prior trials comparing denosumab with other bisphosphonates in patients on GC led to greater spine and hip BMD gains, but there were no significant differences in fracture rates [35]. Trials have shown that denosumab decreases RA erosions [36]. Withdrawal of denosumab therapy is associated with a rebound in vertebral fracture rate, but adverse effects are in general non-significant [37]. Denosumab effect in SSc patients is not currently published.

3.5 Osteoanabolics

Teriparatide and abaloparatide are parathyroid hormone (PTH) analogs that stimulate osteoblast activity resulting in net bone formation [38]. The most common reported adverse events in patients treated with PTH analogs are nausea, pain in the limbs, headache and dizziness. Worsening of calcinosis cutis with teriparatide treatment in osteoporotic patients is reported in case reports [39, 40]. Romosozumab is a monoclonal antibody against sclerostin thereby stimulates osteoblasts with less concomitant activation of osteoclastic activity resulting in significant BMD gains and fracture prevention [41]. These treatments are considered in patients believed to be at very high risk for fracture, including those with a new or recent fracture or significant declining BMD on oral bisphosphonates or denosumab [42].

4. Hormone-based therapies

Raloxifene, a selective estrogen receptor modulator, stabilizes bone density and helps to prevent vertebral fractures in women, but it has not been shown to improve hip fracture rates [43].

American College of Rheumatology (ACR) 2017 Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis suggest it as a treatment option only for postmenopausal women with contraindications to other bone health agents and without thromboembolic risk [13]. Bazedoxifene is a third-generation selective estrogen receptor modulator (SERM) in the US was approved as combination drug along with conjugated estrogens to prevent post-menopausal osteoporosis achieves small but significant increases in the bone mineral density of the lumbar spine but not the total hip [44]. However, in pre-clinical models SERM-class drugs could treat SSc fibrosis [45].

Hypogonadism is a risk factor for osteoporosis. Testosterone treatment may be indicated in men with documented symptomatic androgen deficiency as it has been found to improve BMD but should not be used alone as an osteoporosis agent because there is no long-term anti-fracture efficacy data [46].

5. Lifestyle modification

Patients with SSc should be counseled on tobacco cessation, healthy diet, alcohol reduction, and weight-bearing exercise, especially if they have a reduction on BMD. Poor dietary habits, including high intake of sugar-sweetened beverages, are associated with hyperglycemia can decrease osteoblast proliferation and increase osteoclast activation [47]. A nutritionist is a critical partner on a SSc patient’s team of providers, especially in SSc patients with low BMD [48, 49]. Formal exercise programs are recommended for SSc patients, with a focus on balance and fall prevention [50].

6. Conclusion

Bone health screening is a critical aspect of SSc patient care. However, SSc patients have disease features that are worth considering (Figure 1) [51]. In addition to referral for DXA, screening laboratories are critical to understand potential gastrointestinal and renal involvement that influence treatment decisions. Esophageal disease may limit bisphosphonate compliance, and denosumab is a reasonable choice in SSc patients. While the presence of calcinosis cutis should not limit calcium and vitamin D replacement, the use of PTH analogs may cause a worsening of lesions. SERM may have a beneficial anti-fibrotic effect but require further study and should be balanced against possible thromboembolic risk in these patients with vasculopathy. Healthy diet and weight-bearing exercise should be encouraged by the treating rheumatologist regardless of bone health status, but these become a critical aspect of the care plan when osteoporosis is diagnosed.

Disclosures

None.

Key Points

Bone health assessment, including medical history, screening laboratories, and dual energy X-ray absorptiometry, is a critical aspect of SSc patient care.
Treatment of low bone mineral density once detected can be a challenge and the treating physician should avoid oral bisphosphonates in SSc patients with significant esophageal disease or renal impairment and osteoanabolic therapies in SSc patients with calcinosis.

Atsushi Ajisawa

Chapters authored

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