The prevalence of osteoporosis in COPD generally varies between 21 % and 59 % depending upon the diagnostic methods used, the age and gender of the sample, and the duration and severity of COPD in a study group [47, 48]. The few studies that demonstrated prevalence under 20 % used either quantitative ultrasound in part for the diagnosis, which is not the standard of care, or included subjects with obstructive airflow disease who had not met the definition of “chronic” in terms of disease duration. Although COPD is the third leading cause of death in the United States [49], it is not considered a risk factor for osteoporosis by the American College of Physicians, nor is smoking, despite its close association with COPD [50]. In contrast, the FRAX tool for prediction of fractures includes COPD but not smoking. Selected pulmonary parameters, inactivity, steroids, and other medications are among the risk factors for osteoporosis in those with COPD.

In their 2011 review of a number of studies involving samples of 40 to over 100 subjects, Lehouck et al. [47] found that osteoporosis occurred to a greater degree in subjects with lower forced expiatory volume in 1 second (FEV₁) scores and in those with advanced disease who are awaiting organ transplant [51]. In a study by Silva et al. [52] in which 42 % of subjects with COPD were osteoporotic and another 42 % were osteopenic, a significant correlation was found between femoral neck T-score and body mass index (BMI), with a significant inverse relationship between femoral neck T-score and BODE, a combined value including body mass index, air flow obstruction, dyspnea, and exercise capacity. In addition, correlations were found between a DXA T-score and FEV_1, forced vital capacity (FVC), and percent of predicted diffusing capacity of the lung for carbon monoxide. The severity and rate of progression of COPD would have a marked influence on maintaining BMD.

By contrast, a 2011 study by Graat-Verboom et al. [53] examining 255 outpatients with stable COPD revealed an astonishing 51 % had osteoporosis defined by a combination of spinal x-rays and DXA. A summary of recent studies on prevalence rates is given in Table 3.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has defined four levels of COPD severity, ranked I–IV, the end stage [64]. GOLD rankings take into account extrapulmonary manifestations of COPD, one of which is osteoporosis.

Among the most consistent risk factors for osteoporosis in the COPD population is the prolonged use of oral corticosteroids or glucocorticoids (GCs). An extensive review by van Staa et al. [65] demonstrates that the total cumulative dose of corticosteroids is inversely related to BMD. Although this study was not specifically focused on COPD patients, it does illustrate the substantial risk that COPD patients face in terms of maintaining bone health with cumulative years of GCs use.

The risk of developing osteoporosis with inhaled corticosteroids (ICS), as opposed to oral or intravenous corticosteroids (ICS), appears to be low based on a meta-analysis by Drummond et al. [66] who observed no significant difference in BMD among those COPD subjects using and not using ICS. Similarly, the TORCH trial (Towards a Revolution in COPD Health) [55], involving 658 patients with COPD, found minimal decreases in BMD (1.7–3.2 %) with use of ICS therapy in the first three years. However, the risk for fractures with ICS is increased, according to a number of investigations described in the following section.

As some investigations on COPD patients demonstrate, BMD assessed by DXA measures only bone density, not bone microarchitecture and bone quality. However, the use of DXA as a measure of BMD to determine fracture risk may not be ideal in some settings. Quantitative CT (QCT), an alternative method of assessment, was employed in a large study (n = 3317) dealing with the effect of smoking on both osteoporosis and vertebral fracture risks in patients, with and without COPD [66]. In a smaller companion sample of 111 subjects taken from this larger group, Jaramillo et al. [67] applied both QCT and standard DXA tests, finding that QCT identified more subjects as osteopenic or osteoporotic than did DXA and that these subjects had a greater number of fractures. In this sample, 6 % of the QCT-classified osteopenic subjects and 37 % of those classified as osteoporotic had vertebral fractures. More broadly, the trial concluded that COPD was independently associated with not only low volumetric bone density, after adjusting for race, BMI, smoking, steroid use, and age, but also with an increased prevalence of vertebral fractures, with the highest number of fractures between T6-12, a region that is perhaps better evaluated by quantitative CT than DXA.

In a further analysis of ICS in COPD, Loke et al. [68] evaluated 16 randomized controlled trials (RCTs) and 14 observational studies relating to the use of two different ICS, fluticasone or budesonide, for at least 90 weeks. Findings demonstrated an increased odds ratio (OR) for fractures of 1.27 for all studies and 1.19 for the four trials of greatest duration (three years). The preceding meta-analysis evaluated risks of vertebral and nonvertebral fractures, with evidence demonstrating ICS were associated with both types of fractures. However, no comparison of likelihood of one type of fracture versus another was possible, since the studies used different combinations of ICS or different solo agents.

Clinicians often balance the benefits of steroids for prevention and management of COPD exacerbations against the deleterious effects on other organ systems including bone health. Yet even very low daily doses can have deleterious effects: 2.5 mg/day presents a modest increased risk of fractures, while amounts greater than 7.5 mg/day confer a fivefold increased fracture risk [65, 69]. However, the risk of fractures does dissipate with discontinuation of steroids.

Many different elements—physiologic, environmental, and pharmacological—contribute to osteoporosis in those with COPD and emphysema. Chronic hypoxemia, chronic inflammation, hypogonadism, dietary deficiencies in vitamin D and calcium, chronic use of corticosteroids, and other disease-modifying agents reduced physical activity and contributed to a sedentary lifestyle [70]. Figure 1 illustrates the risk factors for osteoporosis and functional consequences [47].

Liang and Feng [44] have demonstrated a relationship between systemic inflammation of low to moderate grades and low BMD in relatively stable COPD patients. It is known that the inflammatory cytokines, IL-6 and TNF alpha, induce expression of RANKL and RANKL-mediated bone resorption. Chronically elevated stores of these cytokines were found to be associated significantly with low BMD (p = 0.023 and 0.010, respectively) as was the level of C-reactive protein (CRP), falling just short of statistical significance (p = 0.062). These findings held true after adjustment for age, gender, use of inhaled corticosteroids, and severity of airway obstruction. States of chronic inflammation also suppress the WNT/β-catenin signaling pathway that stimulates osteoblasts, thereby contributing to the development of osteoporosis [71].

As in other conditions of inflammation including rheumatic disorders, the use of glucocorticoids (aka corticosteroids) increases expression of RANKL and decreases osteoprotegerin (OPG) [72]. In addition to reducing apoptosis of osteoclasts which resorb bone, enhanced bone resorption occurs, with subsequent inhibition of production and maturation of osteoblasts. These combined effects result in a net loss of bone with ongoing resorption and prolonged inhibition of bone formation. Initial use of GCs adversely alters trabecular bone but prolonged inflammation can also affect cortical bone.

Low vitamin D also compromises optimal absorption of calcium from the gut and influences immature osteoblastic cells to stimulate RANKL which, in turn, stimulates osteoclasts to promote bone resorption. In addition to exerting a direct influence on cells involved in bone metabolism, adequate serum levels vitamin D help to maintain muscle strength, thereby reducing the risk of falls [73–75]. An estimated 20–30 % of patients with COPD have reduced limb muscle strength relative to healthy controls [76].

Finally a mechanical abnormality related to altered lung structure and involving air trapping and parenchymal destruction may account for a substantial portion of bone loss, based on evidence that lung volume reduction surgery in advanced emphysematous patients significantly improves BMD in patients one year after undergoing this procedure [77].

Cystic fibrosis (CF) is an autosomal recessive disorder that affects approximately 30,000 people in the United States and a somewhat higher number throughout the rest of the world [89]. The most common lethal genetic disease in the Caucasian population, it affects the protein known as cystic fibrosis transmembrane conductance regulator (CFTR) which controls the movement of sodium, chloride, and water in and out of cells, predominantly in the lungs but also in the pancreas, digestive system, and liver. With too little or abnormal CFTR, the mucus secreted in these areas becomes thickened, causing obstructions, infection, and loss of function [90].

Generally diagnosed by age two, half of patients with CF recorded in 2014 were, for the first time, over the age of 18, with a survival rate of 39.3 years compared with 29.2 years in 1986. Many patients live well into their 40s and 50s [91]. Advancements in newborn screening programs, leading-edge therapeutic options, and improved management have all contributed to rising life expectancy; however, that lengthened life span has led to an increased occurrence of age-related comorbidities, including CF-associated osteoporosis [92].

As Gore et al. have observed [93], decreased BMD and higher fracture rates occur at a young age, 30 years earlier than in a non-CF population; they increase with age, the severity of the disease, and the use of corticosteroids. Beginning with the 1979 Mischler study [94], subsequent trials have corroborated the finding that CF patients have a demonstrated low BMD. Whereas Mischler used direct photon absorptiometry to find that 44 % of 27 patients (ages 5–24) had significant bone deficiency, Conway et al. [95] employed densitometry and multiple indices of disease severity to determine that, in a sample of 114 adolescents and adults, 79 % of 53 men and 56 % of 61 women had osteopenia or osteoporosis at one or more sites. They further documented a clear relationship between low BMD and disease severity as well as between reduced BMD and corticosteroid use. In terms of bone mineralization, 26 % of 66 patients singled out for this complication had pronounced anterior vertebral collapse, resulting in rib and thoracic compression fractures that restrict both coughing efficiency and the ability to undertake chest physiotherapy.

Further research confirms the marked prevalence of osteoporosis and fractures in patients with CF. In a study involving 50 clinically stable CF adults with 53 controls, Aris et al. [96] demonstrated that the CF cohort experienced accelerated bone breakdown without a compensatory increase in bone formation, suggesting that such factors as inflammatory cytokines and PTH increase osteoclast activity and play a role in CF bone disease [96]. In comparison with age-matched controls, patients with both CF and osteoporosis have a 100-fold increased risk of vertebral fractures and a tenfold increased risk of rib fractures [97]. In a 2010 meta-analysis of young adults with CF (mean age = 18.5–32 years), the prevalence of vertebral fractures varied between 5.0 % and 31.0 %, and the prevalence of nonvertebral fractures was as high as 20–40 %, but it could not be determined whether these fractures were truly osteoporotic [98]. As Goalski and Aris [99] have observed, no association between BMD and fractures has been specifically proved in CF studies. However, the link is so strong outside of CF that it dictates treatment.

Finally, a recent study of areal bone density comparing a cohort of CF adults (ages 18–50) who were evaluated in 1995–1999 (historic) with a comparable cohort examined in 2011–2013 (current) has produced unanticipated, disturbing results [100]. Despite advances in care management and heightened life expectancy, areal BMD was no better in the current cohort than it was 15 years ago. However, the present-day cohort did evidence improvements in pulmonary function, vitamin D deficiency, and secondary hyperparathyroidism. The underlying factors contributing to this static state include difficulty achieving nutritional goals, greater intake of systematic and inhaled glucocorticoids, delayed puberty, and CFTR dysfunction.

As the occurrence of CF-related bone disease continues to rise with increased life expectancy, the number of age-related risk factors increases concomitantly, including those directly related to osteoporosis as well as those unique to CF, specifically the role of the CF transmembrane conductance regulator. The interaction of these factors leads to an uncoupling of the dynamic status of bone turnover, resulting in decreased bone formation and increased bone resorption [101].

Factors contributing to osteoporosis in CF originate in childhood. In comparison with healthy subjects, those with CF during childhood and adolescence fail to achieve adequate bone mass because of the interaction of delayed puberty, chronic infections, and hormonal imbalance [93]; in addition, the BMD in an age group of 4.9–17.8 years was found to decline at a rapid rate of approximately 1 SD every 6–8 years [102]. A high proportion of CF patients—85–90 %—evidence endocrine pancreatic insufficiency leading to digestive problems and malabsorption of vitamins A, E, K, and D. Both vitamin K and vitamin D levels, so critical to bone formation, are significantly reduced in cystic fibrosis. Whereas vitamin K deficiency is linked to low levels of carboxylated osteocalcin, vitamin D deficiency impairs the ability to achieve peak bone mass and limits calcium absorption by increasing bone turnover through PTH stimulation [103].

In severe CF, acute pulmonary exacerbations are associated with higher levels of cytokines (e.g., tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, and IL-6) that stimulate osteoclastic bone resorption and cause bone loss [93]. Corticosteroids employed to improve respiratory function in CF are known to adversely affect bone, with oral corticosteroids decreasing BMD in the lumbar spine and femoral neck and inhaled corticosteroids resulting in low total body BMD [95, 104]. High-dose corticosteroid therapy is particularly important following lung transplantation, but it contributes to a rapid decline in BMD associated with increased fracture risk. In contrast to an earlier prevailing belief that osteoporosis with fractures contraindicates lung transplants, most transplant centers now regard osteoporosis as a “remediable comorbidity,” with only uncontrolled pain related to fractures considered to be a contraindication [105, 106].

Specific to osteoporosis in CF, dysfunction of the CFTR has recently been implicated as another factor leading to bone disease. In trials with knockout mice, the existence of an abnormal CFTR protein called delta F509 was linked with osteopenia, reduced cortical bone, and thinning of the trabecular bone [107], while a study of CF adults revealed that delta 509 mutation is an independent risk factor for osteoporosis [108, 109]. In addition, Shead et al. [110] have demonstrated the presence of CFTR in human osteoblasts, osteocytes, and osteoclasts. Implications of these findings require further research.

In accordance with guidelines established by the Cystic Fibrosis Foundation [111], screening for CF-related bone disease should begin in childhood in order to determine the extent of bone density loss and to implement preventative and treatment measures. A baseline BMD determined by standard dual-energy x-ray absorptiometry (DEXA) of the lumbar spine and hip is recommended for all patients at age 18; children ages eight and over should be tested if they evidence risk factors such as previous history of fractures, delayed FEV₁ <50 % predicted, and glucocorticoids 5 mg/day or more for a minimum of 90 days/year.

In the course of renal disease, a number of circulating inhibitors and promoters work in negative ways to decrease bone formation and bone mineralization (Fig. 4). Fibroblast growth factor FGF23 is increased along with sclerostin, both of which promote bone resorption and bone remodeling, although FGF23 does so only indirectly through mechanisms involving PTH and vitamin D. Produced by osteocytes and osteoblasts, FGF23 exerts a direct action on renal tubules and parathyroid glands. As kidney disease progresses, the number of working nephrons in the kidney continually declines. Hence, more phosphate is excreted by each of the remaining nephrons, a mechanism that is only possible through increased activity of FGF23 and parathyroid hormone (PTH) [122]. The constant elevated production of PTH resulting from hyperplasia of the parathyroid glands results in increased RANKL production. The consequences of increased RANKL in this setting are significant: high turnover renal osteodystrophy, desensitization of the PTH receptor, and excessive bone resorption [121].

Additional effects of actions of FGF23 include inhibition of the enzyme 25-hydroxyvitamin D 1-α hydroxylase that produces calcitriol, resulting in decreased intestinal calcium absorption and ultimately hypocalcemia. This cascade of events also reduces the number of active vitamin D receptors on cells in the parathyroid contributing to more definitive adverse changes in CKD–MBD of those with advanced renal disease [123]. High serum phosphorous, low serum calcium, and low calcitriol levels collectively contribute to persisting and worsening hyperparathyroidism. By controlling the levels of calcium and phosphorous early in the course of CKD, practitioners can help to prevent one of the most severe complications of renal osteodystrophy, i.e., hyperparathyroidism [124].

There are three different types of metabolic disorders in CKD: high bone turnover states, low bone turnover states, and mixed disorders. If hyperparathyroidism is present, a high bone turnover state develops which is characterized by irregular collagen production known as woven bone. In comparison to mineralized bone, woven bone lacks strength because of haphazard orientation of the type I collagen fibers that form osteoid. Furthermore, due to enhanced resorption as compared with formation, bone mass is decreased. In contrast, if the prevailing PTH level is insufficient to overcome PTH resistance characteristic of severe CKD, the result is a low bone turnover state, a condition classified as either adynamic bone or osteomalacia. Adynamic bone is characterized by complete lack of osteoid production and new bone formation, whereas osteomalacia results from normal osteoid production but impaired ability to mineralize the osteoid. In CKD, osteomalacia most frequently occurs from aluminum toxicity. In mixed uremic osteodystrophy, both a mineralization defect and high bone turnover state exist [121]. All three disorders are influenced by the extent of vitamin D metabolic irregularities, any immunosuppressive treatment adversely affecting bone maintenance, dietary restrictions, and associated health problems including diabetes. Table 5 compares the various types of bone turnover pathology seen in CKD [121].

The intact PTH level varies depending on the severity of CKD. Elevated levels of intact PTH are often desired in later stages of CKD (3–5D) in order to have optimal bone health due to the known skeletal resistance to PTH with uremia. Therapy should be aimed at improving calcium, phosphorous, and vitamin D levels, as well as focusing on PTH levels [124]. If intact PTH falls outside the desired range of 2–9 times, the upper limit of normal in a patient with CKD stage 5D, management plans must be further individualized in conjunction with close coordination with the patient’s nephrologist. Nearly all of the laboratory studies and medical treatments desired at this stage of evaluation can be performed in an inpatient rehabilitation setting. Only in cases of severe CKD (stages 3–5D), which are consistently unresponsive to medical interventions including both dialysis adjustments and pharmacologic agents, would a parathyroidectomy need to be considered.

Serum calcium (or ionized calcium if albumin levels are low), phosphorous, intact PTH, and bone-specific alkaline phosphatase should be measured at baseline when GFR falls below 60 ml/min. Serum vitamin D 25OH should be monitored at least twice annually, especially at the end of winter when levels reach their nadir. Due to diurnal, postprandial, and dialysis (pre and post) variability, it is helpful to pick a consistent time for patients to be analyzed and compare those values over months. In addition, titers used by laboratories differ, particularly for vitamin D and alkaline phosphatase. Although P1NP is an alternative marker of bone formation to bone-specific alkaline phosphatase, it is not widely available, takes longer to process and obtain results (often sent out of a clinic to a specialized lab), and is between three and four times the cost of bone-specific alkaline phosphatase [125]. In reality, the most important measures used for day-to-day management of CKD–MBS remain calcium, phosphorous, vitamin D, and PTH.