Non-GCs Drug-Induced Osteoporosis

Abstract

Medications that cause osteoporosis are numerous and common. While helping to correct one problem, they may be putting you at greater risk of having osteoporosis. A variety of drugs may cause bone loss by lowering sex steroid levels (e.g., aromatase inhibitors used in breast cancer and GnRH agonists used in prostate cancer), interfering with vitamin D levels (liver-inducing antiepileptic drugs), or directly affecting bone cells (chemotherapy, phenytoin, or thiazolidinediones) which divert mesenchymal stem cells from osteoblastogenesis to adipocytogenesis, consequently, an imbalance occurs between bone formation and resorption, as well as between soft organic matrix and hard inorganic matrix. Besides effects on the mineralized matrix, interactions with collagen and other nonmineralized matrix components can decrease bone biomechanical competence without affecting bone mineral density (BMD). Here is a quick narrative for a number of disease medications that can cause osteoporosis if taken for long periods without a preventive program of minerals and vitamins. Rheumatoid arthritis, inflammatory bowel disease, asthma, acid reflux, thyroid dysfunctions, seizures, endometriosis, aromatase inhibitors, hypertension, contraceptive Depo-Provera, antidepressant (SSRIs, SNRIs), glitazones for type 2 DM treatment.

1. Introduction

Medications that cause osteoporosis are numerous and common. While helping to correct one problem, they may be putting you at greater risk of having osteoporosis. Several drugs and drug classes can decrease BMD, including thiazolidinediones, and consequently increase fracture risk; other drugs, such as selective serotonin reuptake inhibitors (SSRI), do not necessarily increase bone loss, but they may increase fracture risk, possibly resulting from an increased risk of falls due to effects on postural balance mediated by central nervous system effects. Amiodarone is a potent antiarrhythmic drug. It is a benzofuran-derived, iodine-rich compound with some structural similarity to thyroxine (T4). Amiodarone contains approximately 37% iodine by weight. Each 200-mg tablet is estimated to contain about 75 mg of organic iodide, 8–17% of which is released as free iodide. Thyroid abnormalities have been noted in up to 14–18% of patients receiving long-term amiodarone therapy. 2010 FDA warning: proton pump inhibitors and increased fracture risk revised warning for PPI: possible increased risk of hip, wrist, and spine fractures.

Aromatase inhibitors stop the production of estrogen in postmenopausal women. Aromatase inhibitors work by blocking the enzyme aromatase, which turns the hormone androgen into small amounts of estrogen in the body.

Osteoporosis can arise as a consequence of some rheumatic diseases, as RA itself can contribute to osteoporosis through systemic inflammation; immobility and medications other than glucocorticoids like long-term use of or methotrexate that inhibits osteoblastic differentiation leading to a reduction in bone formation and an increased risk of osteopathy. Patients with IBD are more likely than the general population to experience bone loss due to malnutrition, vitamin D and calcium malabsorption and deficiency, vitamin K insufficiency, immobilization, and underlying inflammatory state.

Long use of such medications leads to decreased bone biomechanical capability and thus a decreased density of bone and an increased risk of fractures.

All patients who have been receiving such medications should undergo a DEXA scan and lateral spine X-ray to check for osteoporosis. People with fragility fractures or at high risk of developing fractures should avoid such medications. Moreover, non-pharmacological measures such as calcium/vitamin D nutrition and exercise should be encouraged. In general, Non-GCs Drug-Induced Osteoporosis is treated with the same medications that are used for general health care when the BMD (T score < 2) or higher.

In this chapter, we aimed to summarize most of these medicines to make them easily accessible for rheumatologists, orthopedists, and anyone else interested in managing osteoporosis (Figure 1).

Figure 1.

Non-GC drug-induced osteoporosis: mode of actions with examples.

2. Amiodarone-induced osteoporosis

Due to its high iodine content and direct harmful effect on the thyroid gland, amiodarone is however linked to a range of side effects, including thyroid dysfunction (both hypo- and hyper-thyroidism).

A strong antiarrhythmic medication called amiodarone is used to treat supraventricular and ventricular tachyarrhythmias. It is an iodine-rich molecule produced from benzofurans that resemble thyroxine structurally in several ways (T4). Iodine makes up roughly 37% of the weight of amiodarone. It is believed that each 200-mg tablet contains 75 mg of organic iodide, of which 8–17% is released as free iodide. Standard maintenance therapy uses 200 mg of amiodarone, which is 100 times the recommended daily intake [1, 2].

Up to 14–18% of patients undergoing long-term amiodarone therapy develop thyroid problems which range from aberrant results from thyroid function tests to overt thyroid dysfunction, which could be one of the following: 1- Amiodarone-induced thyrotoxicosis (AIT) or 2- Amiodarone-induced hypothyroidism (AIH) [3, 4]. Both can appear in thyroid glands that appear to be normal or in glands that already have abnormalities.

2.1 Pathophysiology

The thyroid is subject to a variety of impacts from amiodarone.

1. Amiodarone reduces the peripheral conversion of T4 to (T3) and the elimination of both T4 and reverse T3 by inhibiting type 15′-deiodinase enzyme activity (rT3). As a result, the serum levels of T4 and rT3 rise while T3 levels drop by 20–25%.

2. Amiodarone prevents T4 and T3 from entering peripheral tissue. After 1–4 months of amiodarone therapy, serum T4 levels rise by an average of 40% [2, 5, 6].

3. Thyroid-stimulating hormone (TSH) levels rise as a result of feedback regulation’s inhibition of type 25′-deiodinase enzyme activity in the pituitary during the first 1–3 months. There is no need for T4 replacement in these patients based on this. In 2–3 months, serum TSH levels return to normal as T4 concentrations sufficiently increase to overcome the gap in T3 synthesis. There may be a diminished response of TSH to thyroid-releasing hormone (TRH) [7].

4. Amiodarone and its metabolites may directly damage thyroid follicular cells, resulting in thyroiditis that is destructive.

5. At the cellular level in the heart, amiodarone and its metabolite desethylamiodarone can function as a competitive antagonist of T3 [7].

While a patient is using amiodarone or even months after stopping the medication, thyrotoxicosis might happen. Once treatment has lasted the first 18 months, hypothyroidism is uncommon [8].

2.2 Two forms of AIT have been described

1. Type 1 usually affects patients with latent or preexisting thyroid disorders and is more common in areas of low iodine intake. Type 1 is caused by iodine-induced excess thyroid hormone synthesis and release.

2. Type 2 affects people whose thyroid glands were previously healthy and is brought on by a destructive thyroiditis that causes the thyroid follicular cells to become destroyed and leak preformed thyroid hormones. However, mixed types of AIT with characteristics of destructive processes and excess iodine may develop in an aberrant thyroid gland [9].

2.2.1 AIT signs and symptoms include the following

1. Unaccounted-for weight loss

2. A greater tolerance for heat or perspiration

3. extreme musculature weakness

4. Unknown exhaustion

5. Emotional brittleness

6. Constant stools

7. Oligomenorrhea

8. Panic, trembling, or palpitations [10]

2.2.2 Symptoms of AIH include the following

1. Fatigue

2. Lassitude

3. Intolerance to cold

4. Mental slowness

5. Weakness

6. Constipation

7. Menorrhagia

8. Dry skin [10]

3. Proton-pump inhibitors and risk of fractures

PPIs are among the most frequently recommended treatments worldwide in clinical practice. Although the majority of patients handle PPIs well overall, there is growing concern over a possible link between PPI use and an increased risk of bone fracture [11, 12]. Indeed, the correlation between PPI medication and the incidence of fracture has been documented in numerous observational studies [13, 14, 15]. The findings of each study differ significantly from one another. According to meta-analyses of the evidence, PPI medication is often linked to a higher risk of fracture [16, 17, 18, 19, 20]. The Food and Drug Administration (FDA) also issued a safety advisory in May 2010 addressing a potential increase in fracture risk of hip, wrist, and spine fractures associated with PPI usage and recommended that no more than three 14-day treatment sessions should be taken in a year, based on seven epidemiologic studies and claims data base analysis (no randomized trials), while they recognized that additional data were required [18].

3.1 Pathophysiology

PPIs are strong inhibitors of stomach acid secretion, which is thought to be important for calcium absorption by enhancing the solubility of calcium salts that are insoluble leading to decreases intestinal calcium absorption and ultimately causing a decline in bone mineral density [15]. Regarding the impact of PPI use on calcium absorption, there is a paucity of clinical evidence and inconsistent findings. Furthermore, PPI use may induce hypomagnesemia, which could increase the fracture risk, although this is also controversial [17]. Increased fracture risk after 1–7 years of treatment. Risk factors include age > 50, “high dose” and longer duration. Zhou et al. [20] stated that PPI use for less than a year was also linked to an increased risk of hip fracture. This finding may undermine the idea that PPI use increases the risk of fracture through biochemical mechanisms (such as changes in calcium absorption or bone mineral density). Further research is required to elucidate any other pathways that may exist and have an impact on bone mineralization or bone quality directly [19, 20].

4. Aromatase inhibitors (AIs)-induced bone loss

The majority of adverse reactions to aromatase inhibitors (AIs) affect the musculoskeletal system and can be divided into three groups [21]:

1. Metabolic bone disease, which increases the risk of fractures;

2. Arthralgia syndrome; and

3. Autoimmune rheumatic illnesses.

All of these adverse outcomes begin to manifest after varying amounts of time have passed since the start of treatment with AIs. Although the precise pathophysiology is not fully understood, the pathogenetic pathways endorsed to explain these disorders are primarily related to the estrogen deficiency caused by a prolonged AIs treatment [21].

4.1 Pathophysiology of AIs-induced bone loss

The hypoestrogenic state brought on by AIs accelerates bone loss at the areas with high levels of trabecularity (vertebral body) and significantly increases bone resorption. In fact, a lack of estrogen alters the dynamic equilibrium between the osteoblasts and osteoclasts activities. Tumor necrosis factor (TNF) and receptor activator of nuclear factor-kB ligand (RANKL), which serve as the main mediators for osteoclast activation and maturation, are more likely to be secreted by T cells as a result of this situation. The equilibrium between RANKL and osteoprotegerin (OPG), a soluble RANKL decoy receptor that blocks the binding of RANK to RANKL and inhibits the osteoclast activity, actually maintains the proper functioning of osteoblasts and osteoclasts [22, 23, 24, 25, 26, 27, 28].

Finally, the pathologic bone remodeling seen following AIs therapy may be caused by genetic variations of the RANK/RANKL/OPG pathway. The RANKL/OPG ratio was shown to be altered as a result of the rs7984870 SNP in the RANKL gene, which had detrimental effects on bone health. Despite the fact that Exemestane (Aromasin) appeared to have a bone-sparing impact in preclinical investigations, which is likely due to its androgenic nature, bone loss was documented for all AIs in clinical trials, which largely evaluated these medication’s effectiveness in breast cancer. According to some reports, the rate of bone loss following AIs therapy is two times higher than in postmenopausal women in good health [25]. This data led investigators to propose that several pathophysiological mechanisms, such as those influencing bone geometry, bone microstructure, other aspects of bone quality, may be responsible for bone fragility in women who have received AIs treatment.

5. Rheumatoid disease and methotrexate

Low-dose MTX is regarded as an effective RA treatment since it reduces joint stiffness, pain, and inflammation while also greatly delaying bone deterioration. It is generally known that generalized osteoporosis can arise in RA per se. Three main causes have been proposed as the mechanism of this osteoporosis [29]:

1. Systemic rheumatoid inflammation;

2. Immobility; and

3. Medications like corticosteroids.

Since MTX reduces rheumatic inflammation and permits an increase in physical activity, this medication may help with OP brought on by RA. However, MTX has been shown to have a negative impact on bone among RA patients and animal models. Sally et al. described two cases of MTX osteopathy with fractures in rheumatoid arthritis patients getting long-term low-dose MTX treatment. MTX osteopathy has been mentioned in an increasing number of papers [30]. Even though glucocorticoids prefer cancellous bone, MTX-induced bone loss and fractures mostly affected cortical bone. Patients with rheumatic disease who underwent histological investigation revealed that MTX osteopathy has impaired bone formation, as evidenced by a decreased osteoblast surface and a lower mineral apposition rate. Additionally, May et al. observed that low-dose MTX impairs bone formation and increases bone resorption in both normal and ovariectomized mice, resulting in osteopenia [31, 32]. However, MTX’s inhibition of the development of marrow osteoblast precursor cells leaves unclear the particular mechanism by which it reduces bone production. Additionally, MTX significantly reduced ALP activity and prevented calcified nodules from forming in cultures of marrow stromal cells. Given that May et al. found that MTX inhibits matrix mineralization using terminally developed osteoblasts, it is possible that MTX also suppresses mature osteoblasts. The transcription factor Cbfa1 has recently been identified as a key player in osteoblastogenesis. Therefore, a study into how MTX affects osteoprogenitor cells’ expression of Cbfa1 may be useful for understanding the molecular basis of MTX osteopathy. Furthermore, bone metabolism is hampered by disease activity [29, 30, 31, 32, 33, 34].

6. Inflammatory bowel disease (IBD)

IBD, which is predominantly made up of Crohn’s disease (CD) and ulcerative colitis (UC), is linked to a number of systemic problems, including extraintestinal manifestations (EIMs) which are prevalent among 40% of IBD patients. The most well-known (EIMs) are as follows:

1. Liver illnesses (primary sclerosing cholangitis and primary biliary cirrhosis),

2. Articular symptoms,

3. Skin lesions (such as erythema nodosum and pyoderma gangrenosum) [35, 36, 37].

Patients with IBD are more likely than the general population to experience bone loss. Osteopenia and osteoporosis are manifested by a decrease in bone mineral density (BMD), caused by chronic inflammation [38, 39]. According to cross-sectional studies, IBD patients have a wide-ranging prevalence of low BMD. Depending on the study population, location, and methodology, the prevalence of osteopenia and osteoporosis can range from 22% to 77% and 17% to 41%, respectively [40].

6.1 Pathophysiology of osteoporosis in inflammatory bowel disease

In addition to corticosteroid use, aging, smoking, malnutrition, vitamin D and calcium malabsorption and deficiency, immobility, and the underlying inflammatory condition are risk factors for osteoporosis in inflammatory bowel disease. According to research by Bernstein et al., patients with IBD have a 40% higher incidence of fractures than the general population [41].

6.2 Inflammation

Numerous factors have a significant impact on bone metabolism, but there is growing evidence that inflammation itself has a role in osteoporosis among patients with IBD. Even without the use of drugs like corticosteroids, some investigations in newly diagnosed patients with IBD showed a decline in BMD. Osteoporosis and a increased fracture incidence are associated with a number of chronic inflammatory diseases [42, 43, 44]. The production of pro-inflammatory cytokines including interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-), IL-6, IL-11, IL-15, and IL-17, is linked to increased bone resorption and decreased bone formation. RANK/RANKL/osteoprotegerin is probably the major mechanism implicated in the onset of osteoporosis in IBD and other inflammatory illnesses. In a study of 137 IBD patients, Reffitt et al. found that those with prolonged illness remission had higher BMD [45, 46, 47].

6.3 Smoking

The amount and duration of smoking may influence how smoking affects bones. Smoking may affect 25 hydroxylases in the liver, which lowers serum 25-hydroxyvitamin D levels, altering the hepatic metabolism of vitamin D. This may explain why smoking and vitamin D deficiency appear to be related. Also, there is proof that smoking can affects the gastrointestinal absorption of calcium. Although it is debatable whether smoking affects estradiol levels, certain research studies have shown that smoking affects the production and metabolism of estrogen. Smoking accelerates the hepatic metabolism of estradiol and nicotine may diminish the synthesis of estrogen. Also, smokers have greater serum levels of the sex hormone-binding protein, which lowers free estradiol levels. All IBD patients should be encouraged to quit smoking, though, as it lowers the risk of secondary consequences such as heart disease, lung cancer, and changes in bone health [48, 49, 50].

6.4 Malnutrition

Nutritional deficits linked to inflammatory bowel disorders have been mentioned as additional pathogenic pathways causing low bone mineral density. There have been reports of calcium insufficiency in Crohn’s disease due to either inadequate intake or poor intestinal absorption [51, 52, 53].

Patients with ulcerative colitis and/or Crohn’s disease have been found to have more vitamin D deficiencies compared to the control healthy population reference range. Elevated levels of bone turnover markers coexist with decreased vitamin D level in Crohn’s disease patients compared to controls. In general, patients with inflammatory bowel disease have lower vitamin D status for a number of reasons, including [54]: lack of vitamin D lowers calcium levels and triggers secondary hyperparathyroidism, which in turn promotes osteoclastogenesis, increases bone resorption, and causes osteopenia and osteoporosis [55].

1. Decreased efficiency of intestinal absorption of vitamin D due to ileopathy,

2. Disrupted enterohepatic circulation of vitamin D,

3. Decreased dietary intake,

4. Decreased sun exposure, and

5. Renal insufficiency.

Vitamin K insufficiency may potentially have a role in osteopenia related to IBD. Because of ileopathy, some patients may absorb this fat-soluble vitamin. However, the discrepancies in vitamin K status between patients with ulcerative colitis and Crohn’s disease may result from changed bacterial flora that produces less vitamin K. Additionally, it is likely that antibiotics, which are frequently used to treat inflammatory bowel disease patients, could eradicate flora that produces vitamin K [54, 56].

7. Impaired bone health and seizures

Long-term use of anti-seizure medications (ASM) has been linked in numerous studies to the development of osteoporosis, which affects between 11% and 31% of epilepsy patients and increases fracture risk by 2–6 times compared to the general population. The increased risk of fractures in epileptic patients can be attributed to a number of factors, such as fractures brought on by seizures and a higher chance of falling due to both the convulsions themselves and the adverse effect of ASM on balance [57, 58, 59, 60, 61, 62]. There are other factors that contribute to the increased fracture risk in individuals with epilepsy, as evidenced by the fact that seizure-related fractures in people with epilepsy only make up 25–43% of all fractures. Comparing enzyme-inducing ASM (EIASM) to non-enzyme-inducing ASM (NEIASM), previous research studies have demonstrated that EIASM has a deleterious impact on bone mass and the onset of osteoporosis. ASM polytherapy has additionally been linked to osteopenia [63, 64, 65, 66].

7.1 Pathophysiological mechanisms for increased fracture risk in patients with seizures

ASM has been linked to numerous studies of negative effects on bone strength. Although the precise mechanism is not entirely understood, ASM may impact bone quality and bone mass through a variety of methods. But it is widely accepted that certain medications, particularly the EIASM such as carbamazepine and phenytoin, stimulate the hepatic cytochrome P450 system, leading to a variety of endocrine complications [64, 65]. Among these include altered sex hormone-binding globulin concentrations and sex hormone disturbances, but most frequently, EIASM therapy has been proven to cause increased vitamin D metabolism, low vitamin D levels, impaired calcium absorption, and resultant hypocalcemia. These modifications lead to secondary hyperparathyroidism and osteoclastic bone resorption that is activated by parathyroid hormone (PTH), which causes bone loss and decreased bone mineralization [66, 67, 68, 69]. This is in line with the common observation that patients with epilepsy have a tendency to have lower BMD, lower levels of 25-OH vitamin D, and higher levels of alkaline phosphatase and PTH. Additionally, a number of ASM carbamazepine, phenytoin, and phenobarbital have unfavorable direct effects on bone metabolism including osteoblast inhibition and osteoclast stimulation [70, 71, 72].

8. Hypertension and osteoporotic fracture

Osteoporosis and hypertension are common and frequently comorbid disorders in the aged population. Among elderly people, hypertension affects 20–40% of people. Similar to hypertension, osteoporosis affects 20–30% of postmenopausal women globally [73, 74].

8.1 Pathophysiological mechanisms for increased fracture risk in patients with hypertension

According to recent studies, both disorders may have the same etiopathology [75]. Additionally, some hypotensive medications may influence bone mineral density and exacerbate osteoporosis. There are several genetic and etiological similarities between osteoporosis and hypertension. Aging, menopause, and physical inactivity are risk factors for both hypertension and osteoporosis. Human and animal studies have shown that elevated blood pressure is linked to aberrant calcium metabolism, which increases urine calcium loss [76, 77, 78, 79]. These hypertension-related anomalies may ultimately attribute to increased bone loss and decreased bone mineral density (BMD). The overall cumulative incidence of any fracture, hip fracture, and clinical vertebral fracture for men with hypertension was16.3, 3.3, and 5.7 per 1000 person-years compared with 11.3, 2.8, and 4.5 per 1000 person-years for those without hypertension, respectively [80, 81, 82, 83, 84].

In women, additionally, the cumulative total fracture incidence was greater in the hypertensive group compared to the non-hypertensive group (27.6 vs. 21.6 per 1000 person-years for any fracture; 5.7 vs. 1.1 for hip fracture, and 9.3 vs. 8.8 for vertebral fracture) [85].

In contrast to the non-hypertensive group, the cumulative incidence of any hip fracture in women was significantly higher in the hypertensive group [86].

There is a physiologic basis for the association between hypertension and osteoporosis. High blood pressure is linked to increased urinary calcium loss, which impairs the calcium balance necessary for bone remodeling. In fact, an epidemiological study discovered that elevated blood pressure was associated with an increased rate of mineral loss from the bone [87]. Furthermore, high levels of the parathyroid hormone are linked to hypertension and accelerated bone turnover, reducing bone mass, and bone quality. Finally, high blood pressure may gradually harm brain regions involved in balance and gait regulation, which could increase the risk of falls and consequent fractures. These findings imply that appropriately managed blood pressure may potentially promote bone health and protection against fragility fracture given those two closely associated medical problems [88, 89, 90].

9. Serotonin reuptake inhibitors and bone health

Anhedonia, insomnia, anorexia, fatigue, and cognitive dysfunction are symptoms of major depressive disorder (MDD). Osteoporosis and fractures are more likely to occur in people with MDD [91, 92, 93, 94].

SSRIs are associated with an increased fracture risk compared to nonusers, according to a number of observational studies [95, 96, 97, 98]. Comparing 124,655 fracture cases with 373,962 controls, Danish national registers found that the use of SSRIs increased the risk of hip and vertebral fractures [99, 100, 101, 102]. A Dutch study found that SSRI use was associated with an early increase in fracture risk, which peaked within 8 months of use but decreased after discontinuation. The risk of fracture among old patients taking SSRIs is almost threefold in Taiwanese case–control studies [103].

In a cross-sectional study of 5995 patients, SSRIs significantly reduced hip BMD (4%) and spine BMD (6%) compared with nonusers. This was further confirmed in a cohort study of nearly 3000 women divided into three groups: SSRI users (198), tricyclic antidepressants (TCA) users (118), and nonusers (2406). After 5 years, SSRI users had the greatest bone loss (0.8% decrease in BMD). Rauma et al. reported reduced BMD in 928 men receiving SSRIs or SNRIs, but not in TCAs users [102, 104, 105].

9.1 Pathophysiology of serotonin reuptake inhibitors and bone health

Besides hypothalamic–pituitary–adrenal (HPA) axis dysregulation and other hormonal abnormalities, MDD-related lifestyle factors such as poor diet, lack of physical activity, and smoking may also contribute to bone mineralization problems [103, 106, 107, 108, 109]. Psychotropic medications, especially selective serotonin reuptake inhibitors (SSRI), can also increase fracture risks [103, 104, 105, 106]. Serotonin receptors, neurotransmitters, and transporters have been discovered in osteoblasts and osteoclasts since 2001. Gut bacteria synthesize 95% of serotonin [97, 110, 111]. Gut and brain serotonin was found to have different actions on the bone metabolism by acting through different pathways as follows [112]:

1. Gut-derived serotonin reduces osteoblast proliferation, which causes bone loss. In addition to providing signals to osteoblasts through its binding to the receptor Htr1b located on their surface, serotonin inhibits phosphorylation of cAMP responsive element binding protein (CREB) by phosphokinase A (PKA), resulting in decreased expression of cyclin genes and reduced osteoblast proliferation. A crucial role is played by Wnt-catenin signaling in this system since it regulates osteoblast differentiation, proliferation, survival, and bone formation [112, 113, 114, 115].

2. Brain-derived serotonin reduces sympathetic output, which favors bone growth. On the other hand, brain-derived serotonin communicates with the ventromedial hypothalamic neurons via Htr2c receptors to decrease the sympathetic output and increase bone formation [112, 116].

3. SSRIs may act independently on osteoclast’s Ca calmodulin-dependent activation of c-FoseNfatc1 cascade leading to decreased bone resorption. For the shorter duration of use of SSRI, the independent effect on the bone, i.e., decreases in bone resorption predominate, while on long-term use, both independent and serotonin-mediated effects counteract each other leading to bone loss [112, 117].

10. Diabetes and bone fragility

Both osteoporosis and diabetes mellitus are widespread chronic diseases that affect the elders. A considerable number of the population who are at risk for osteoporosis is expected to have a corresponding diabetes because the incidence of both diseases might be as high as 35–40% [118, 119, 120, 121].

With a fracture relative risk (RR) ranging from 1.5 to 3, it is clear that type 2 diabetes is linked to a higher risk of fractures. This appears to be more prevalent in older persons with poorly controlled diabetes and a longer disease duration (>5 years) [120, 121, 122, 123, 124].

Diabetic osteoporosis and diabetic bone disease have been proposed, but they are still not commonly used, in persons who have had diabetes for longer than 10 years [125, 126].

10.1 The pathophysiological mechanisms underlying bone fragility in T2DM

The main causes of T2DM-induced bone fragility comprise chronic hyperglycemia, advanced glycation end (AGE) product accumulation, insulin resistance, altered bone marrow adiposity, inflammatory agents, adipokines generated by visceral fat, and oxidative stress [119].

10.1.1 Hyperglycemia

Exerts both direct and indirect effects on the osteoblastic differentiation and function. Differentiation of bone marrow mesenchymal cells is shifted toward adipogenesis rather than osteogenesis in the presence of hyperglycemia due to:

1. Upregulation of the transcription factor peroxisome proliferator activated receptor-γ (PPAR-γ), which promotes adipogenesis,

2. Downregulation of Runx2/core-binding factor α1 (Cbfα1), which regulates osteoblast differentiation and maturation [124]. Moreover, increased cytokine levels have been shown to suppress osteoblast differentiation and accelerate osteoclastogenesis [125, 126].

10.1.2 AGEs accumulation

By crosslinking with the collagen fibers in bone, AGEs harm the bone by causing microarchitectural degeneration and increased bone fragility [127]. Studies conducted in vitro have demonstrated that AGEs also enhance osteocyte sclerostin expression, a potent inhibitor of bone formation [119, 128].

10.1.3 Insulin resistance

The development of insulin resistance may be one of those deleterious effects on the bone health. It is postulated that decreased muscle strength secondary to decreased glucose uptake by muscles can compromise skeletal loading [119]. Receptors for glucagon-like peptide-1 (GLP-1) are normally also expressed on bone marrow stromal cells and immature osteoblasts, and GLP1 has been shown to stimulate the proliferation of mesenchymal stem cells and inhibit their differentiation into adipocytes [119, 129].

10.1.4 Microarchitecture abnormalities

Diabetes alone degrades the organic composition and strength of bone, which has an impact on its biomechanical qualities [124]. Long-term diabetes compromises bone collagen microstructure, mineralization, and bone strength. Increased porosity and decreased cortical density are two changes in the bone structure associated with T2DM. These elements lead to abnormal bone architecture, which lowers bone’s ability to withstand mechanical stress and increases the risk of fragility fractures [119].

10.1.5 Anti-diabetes medications

Thiazolidinediones (TZDs, glitazones) enhance insulin sensitivity and beta cell response to a glucose load by acting as agonists of nuclear peroxisome proliferator-activated receptor gamma (PPAR-Ƴ). The differentiation of precursor cells into osteoblasts depends heavily on PPAR-Ƴ, which is expressed in osteoblasts, osteoclasts, and stromal cells of the bone marrow. Adipogenesis is enhanced by PPAR-Ƴ activation, which also inhibits osteoblastogenesis [130]. The ADOPT trial was the first to report a link between TZDs and an elevated risk of fracture [130, 131]. When compared to metformin and glyburide treatment arms, the incidence of fracture in the lower and upper limbs was roughly twice as high in women using rosiglitazone [132]. The RECORD study displayed that rosiglitazone was associated with an increased risk of fractures (10.7%) as compared to the combination of metformin/sulfonylurea (6.8%) [130]. Both rosiglitazone and pioglitazone were associated with a significantly increased risk of fractures [133]. In men with type 2 diabetes, rosiglitazone has been linked to a higher risk of vertebral fractures [134, 135]. In the ACCORD bone research, female patients who stopped taking TZD had a reduced incidence of fracture after 1–2 years [136].

11. Conclusion

A number of medications we use on a daily basis can negatively affect bone health and lead to bone loss. Collagen and other organic compounds of the matrix may also be affected, as well as mineral density, trabecular structure, and hydroxyapatite. Additionally, cellular turnover may be affected, leading to an imbalance between bone formation and resorption as well as between organic and inorganic matrix composition. Consequently, the biomechanical ability of bone is diminished, resulting in decreased bone density and an increased risk of fracture. Additionally, even in the presence of normal bone biomechanical competence, some drugs may increase the risk of falls and fractures.

A variety of drugs may cause bone loss by: 1. Lowering estrogen levels (e.g., aromatase inhibitors used in breast cancer, GnRH agonists used in prostate cancer). 2. Interfering with vitamin D levels (Enzyme-Inducing Anti-Seizure Medications), EIASM therapy has been proven to cause increased vitamin D metabolism, low vitamin D levels, impaired calcium absorption, and resultant hypocalcemia leading to secondary hyperparathyroidism and increased osteoclastic bone resorption. 3. Directly affecting bone cells (chemotherapy, phenytoin, or thiazolidinediones) which divert mesenchymal stem cells from osteoblastogenesis to adipocytogenesis, consequently, an imbalance occurs between bone formation and resorption, as well as between soft organic matrix and hard inorganic matrix. Besides effects on the mineralized matrix, interactions with collagen and other nonmineralized matrix components can decrease bone biomechanical competence without affecting bone mineral density (BMD). 4. Thyroid dysfunction caused by long-term use of (anti-arrhythmic drug amiodarone) that can affect bone health might happen, though as follows: 1- Amiodarone-induced thyrotoxicosis (AIT) or 2- Amiodarone-induced hypothyroidism (AIH). 5. Strong inhibitors of stomach acid secretion (PPIs), which is thought to be important for calcium absorption by enhancing the solubility of calcium salts that are insoluble leading to decreases intestinal calcium absorption, and ultimately causing a decline in bone mineral density. 6. MTX treatment may reduce osteoblastic differentiation, which would then lead to a reduction in bone formation and an increased risk of osteopathy. To clarify the long-term effects of MTX on bone density of both axial and peripheral bones, a longitudinal investigation is consequently required. 7. Patients with IBD are more likely than general population to experience bone loss due to malnutrition, vitamin D and calcium malabsorption and deficiency, vitamin K insufficiency, immobilization, underlying inflammatory state. 8. High blood pressure is linked to increased urinary calcium loss, which impairs the calcium balance necessary for bone remodeling. Furthermore, high levels of the parathyroid hormone are linked to hypertension and accelerated bone turnover, reducing bone mass and bone quality. Finally, high blood pressure may gradually harm brain regions involved in balance and gait regulation, which could increase the risk of falls and consequent fractures. 9. Psychotropic medications, especially selective serotonin reuptake inhibitors (SSRIs), can increase fracture risk. Gut-derived serotonin reduces osteoblast proliferation, which causes bone loss. 10. Thiazolidinediones (TZDs, Glitazones) enhance insulin sensitivity and beta cell response to a glucose load by acting as agonists of nuclear peroxisome proliferator-activated receptor gamma (PPAR-Ƴ), leading to enhanced adipogenesis and inhibited osteoblastogenesis.