Department of Rehabilitation Medicine, Thomas Jefferson University/Magee Rehabilitation Hospital, Philadelphia, PA, USA
Department of Rehabilitation Medicine, Thomas Jefferson University, Philadelphia, PA, USA
Christina V. Oleson
Peripheral neuropathy, characterized by damage or destruction of neurons that determines how they communicate with each other, affects three types of nerves: sensory, motor, and autonomic (nerves that control involuntary or semi-voluntary function such as heart rate, blood pressure, and digestion) . Damage to only one nerve is termed a mononeuropathy; mononeuritis multiplex neuropathy occurs when two or more isolated nerves in different part of the body are damaged; polyneuropathy implies the involvement of multiple nerves simultaneously. As opposed to hereditary neuropathy, acquired neuropathy has a number of causal factors including systemic diseases, medications and toxins, trauma, infections, autoimmune disorders, and vitamin imbalances. Its symptoms include numbness and tingling in the hands and feet, severe pain or the inability to feel pain at all, loss of coordination and reflexes, and muscle weakness [2, 3]. Diabetes, the primary cause of peripheral neuropathy, will be considered in this chapter together with critical illness polymyopathy and polyneuropathy and their association with immobility and medications. Two autoimmune disorders, Guillain–Barre syndrome and inflammatory demyelinating polyradiculoneuropathy, will also be discussed.
Diabetes mellitus (DM) is a disease of pandemic proportions in both the developed and developing nations. The International Diabetes Foundation reports that, as of 2014, some 387 million people worldwide were living with diabetes, with an estimated increase to 592 million by 2035 . If the current trend persists, diabetes prevalence in the United States will likely increase from 14 % in 2010 to 21 %, and, possibly, 33 % by 2050, depending upon the health of an aging population, the longevity of diabetic patients, and the survival of increasing numbers of high-risk minority groups .
Diabetes is divided into type 1 and type 2 variants, previously known as insulin- and non-insulin-dependent diabetes mellitus; the potential for hyperglycemia is present in both . Type 1 diabetes (T1DM), affecting approximately 5–10 % of all diabetic individuals, is related to a rheumatoid-like autoimmune reaction that destroys the beta cells of the pancreas, leading to decreased production of insulin and, within a short time, total cessation of production. Formerly known as juvenile diabetes, it commonly begins in childhood but can develop in older adults as well. Type 1 diabetes cannot be prevented but can be controlled with daily insulin injections or an insulin pump .
In type 2 diabetes (T2DM), occurring in 90–95 % of diabetic patients, the pancreas continues to produce insulin but encounters peripheral receptor resistance/insulin resistance which occurs when fat, muscle, and liver cells fail to respond to insulin, preventing blood sugar from entering these cells as stored energy and leading to a buildup of sugar in the blood, resulting in hyperglycemia. Although the pancreas responds initially by producing more insulin, in time it cannot create a sufficient amount to meet the body’s needs. Some 37 % of adults over the age of 20 have early signs of developing insulin resistance (prediabetes) and are at high risk for developing T2DM [7, 8], a condition that particularly targets the overweight and obese population. T2DM can be effectively treated with lifestyle changes including loss of weight, improved diet, and increased levels of physical activity. In addition, metformin, (Glucophage) used alone or with insulin, increases insulin sensitivity and reduces glucose levels without risk of hypoglycemia and weight gain.
Diabetes is associated with a number of health complications including cardiovascular diseases such as heart attack and stroke, kidney disease, blindness and other vision problems, and, the most common complication, peripheral neuropathy. The symptoms of peripheral neuropathy are related to the types of nerves involved, be they sensory, motor, autonomic, or a combination. The longer the duration of diabetes, the greater the risk of diabetic neuropathy. Caused by a number of factors, principally high glucose levels and high lipid levels, diabetic neuropathies are diagnosed on the basis of signs and symptoms including tingling, burning, numbness, and muscle weakness in the extremities as well as problems with coordination, balance, and walking; laboratory tests and electrodiagnostic findings are also employed .
The most common diabetic neuropathy, known as chronic distal sensorimotor symmetrical polyneuropathy (DSPN), impacts up to 50 % of diabetes patients; it is commonly manifested by burning and a deep aching pain in the feet and lower limbs and occurs in a relatively symmetrical manner on both sides of the body. DSPN contributes to an increased risk of foot ulceration and Charcot osteoarthropathy, the progressive destruction of bone and joint integrity, and it remains the leading cause of lower leg amputation .
Etiology and Pathophysiology of Osteoporosis in Diabetes
Both T1DM and T2DM have serious effects on the skeleton, with bone formation, bone microarchitecture, and bone quality altered in both forms. In terms of bone density, evidence shows a decrease in BMD in T1DM and an increase in T2DM. An increased risk of bone fractures has been found in both but to a lesser degree in T2DM. Given the different pathogenesis of T1DM and T2DM, no uniform entity of diabetic osteopathy exists . Nearly 70 years ago, before the development of dual x-ray absorptiometry, Albright and Reifenstein first demonstrated an association between reduced bone mass and poor glycemic control in childhood diabetes. In the years since, numerous trials have been conducted to examine the nature and extent of bone mineral density and fractures in both types of diabetes; some generalizations have emerged but, to a considerable extent, the results remain inconclusive.
Mechanisms of Diabetic Bone Disease
Diabetes mellitus affects bone through the following mechanisms :
Direct metabolic influence of insulin insufficiency on osteoblastic and osteoclastic function
Alterations in endocrine secretagogues by pancreatic beta cells, particularly amylin, causing decreased bone integrity (particularly in T1DM)
Impact of peripheral neuropathy on proprioception and activity levels
Relation between bone loss and both vascular dysfunction and impaired bone microcirculation evident in hyperglycemia
Contribution to diabetic retinopathy, resulting in decreased function and disuse osteopenia and osteoporosis from reduced immobility in setting of visual impairment
Effect of diabetes medications on bone pathology
Whereas T1DM is widely associated with bone loss and decreased osteoblast activity, T2DM is characterized by preserved-to-increased bone mineral density. As Vestergaard has determined , bone mineral density is reduced by 0.2 Z– scores in the hip and spine in T1DM, while it is increased by 0.3–0.4 Z– scores in T2DM. Yet, in spite of this data, the fracture rate in T2DM is increased over that of the normal population, indicating that the structural strength of bone is impaired.
In this section we will review the mechanisms associated with diabetic bone loss. Given the complex relationship between bone density and fracture risk, it should be emphasized that BMD is only one of the variables responsible for bone strength and quality. Understanding the mechanisms underlying the diabetes–bone relationship and advancing studies of this interaction are critical to the development of new therapies to restore bone loss, particularly as the human life span increases, with a concomitant rise in diabetes complications associated with aging. The following discussion focuses on the effect of diabetes on bone primarily in T1DM with references to T2DM as applicable.
Insulin and Insulin Secretagogues
Historically, as well as in recent years, the majority of studies focusing on the state of bone in T1DM have found decreased BMD in both the spine and hip. Osteopenia is present in about 50–60 % of people with T1DM with osteoporosis occurring in 14–20 % of cases . Both osteopenia and osteoporosis are more prevalent in men than in women. One investigation reported that 14 % of the male patients and none of the females met the criteria for osteoporosis . Similar trends for osteopenia have also been reported for diabetic men versus women . Estrogen may also exert a protective effect on women.
Patients who develop T1DM in childhood and adolescence experience frequent episodes of prolonged bone loss, negatively affecting their ability to attain peak bone mass. Insulin is thought to exert an anabolic effect on bone formation based on data indicating that decreased adolescent growth velocity leads to insulin sufficiency which, in turn, impairs osteoblastic function and produces abnormalities of bone microarchitecture . A 7-year prospective study of BMD in T1DM found that intensive insulin therapy significantly increased body mass index and stabilized BMD at all sites, although patients with retinopathy continued to lose body mass .
In addition to insulin, T1DM patients are unable to produce the insulin secretagogue, amylin—a peptide hormone co-secreted with insulin by the beta cells in the pancreas. Amylin enables blood glucose levels to remain relatively stable by slowing digestion, inhibiting secretion of glucagon (a pancreatic hormone that raises blood glucose levels), and enhancing satiety, thereby limiting the possibility of blood glucose “spikes” . In fact, in animal models, supplementation of amylin maintained bone-mass-inhibited biochemical markers of bone reabsorption, and stimulated elevated bone formation . Other secretagogues involved in bone regulation but inhibited in T1DM are glucagon-like polypeptide 2 (GLP2) and gastric inhibitory peptide (GIP). GLP2 receptors have been found on osteoclasts, and their activation is associated with reduced bone reabsorption. GIP receptors are present on osteoblasts, and their activation results in increased secretion of type 1 collagen . It is unclear if the underlying autoimmune process that causes T1DM plays a role in bone metabolism. Table 1 [15, 18, 22–26] describes bone changes in patients with T1DM.
Bone changes in patients with type I diabetes mellitus
Age (range in years)
Age (mean in years)
Mean duration follow-up (years)
Hamilton et al.  (2008)
When compared with age-matched control subjects, adult males with T1DM had lower BMD (hip, femoral neck, spine) (P ≤ 0.048). No significant difference in terms of BMD between females with T1DM versus age-matched control subjects
Lumachi et al.  (2009)
~60 % lower BMD was found in patients with T1DM when compared to age-matched control subjects
Rozadilla et al.  (2000)
Retinopathy found to be associated with low BMD. Osteoporosis present in 3 %. Decreased lumbar spine BMD. No significant decreased of BMD in the femoral neck of patients with T1DM
Munoz-Torres et al.  (1996)
Decreased lumbar spine and femoral neck BMD in patients with T1DM. Osteoporosis present in 19 %. Retinopathy, active smoking, and neuropathy were also associated with decreased BMD
Campos Pastor et al.  (2000)
Retinopathy and poor glycemic control were associated with higher rates of osteopenia and osteoporosis (72 % vs. 53 % without retinopathy); benefits of intensive insulin therapy
Kemink et al.  (2000)
Decreased lumbar spine and femoral neck BMD in patients with T1DM. Osteopenia associated with decreased serum levels of IGF-1 and bone formation markers
Tuominen et al.  (1999)
Decreased (6.8 in females and 7.6 % in males) femoral neck BMD when compared with age-matched control subjects
Hyperglycemia exerts adverse effects on both T1DM and T2DM . It leads to nonenzymatic glycosylation of various bone proteins including type 1 collagen, a condition that may impair bone quality . On a cellular level, diabetes is believed to stimulate bone reabsorption by increasing both the number of osteoclasts and their activity through functions involving tumor necrosis factor alpha (TNF-α), macrophage colony-stimulating factor (M-CSF), and the receptor activator of nuclear factor-kB ligand (RANKL). These cytokines activate osteoclast proliferation and differentiation. As described in earlier chapters of this text, hyperglycemia also suppresses osteoblastic function by decreasing runt-related transcription factor 2 (RUNX2), decreasing osteocalcin and osteopontin expression, and reducing osteoblast proliferation. Due to an adverse effect on bone microcirculation, hyperglycemia reduces neurovascularization, thereby decreasing bone formation and impeding bone repair. The cumulative effect of these actions is a net decrease in bone formation.
Indicators of Bone Health
The sympathetic nervous system is thought to have a positive effect on maintenance of bone density but is impaired in the setting of neuropathy, common in both T1DM and T2DM. Research by Rix et al. shows that peripheral neuropathy in T1DM is associated with a greater risk of reduced bone mass in the spine, femur, and distal forearm, indicating that it may be an independent risk factor for reduced BMD not only as a localized process in the affected limbs but in the skeleton more generally . Both diabetic neuropathy and retinopathy may also lower BMD by reducing physical activity needed to build bone and muscle strength as well as by increasing fall risk and resulting fractures.
At the same time, a meta-analysis of studies examining the relation between neuropathy and indicators of bone health in diabetes found no significant association with poor peripheral bone health in seven of the ten studies reviewed . However, four of the ten studies did find an association between poor bone health in patients with neuropathy compared to those without neuropathy. Moreover, the authors acknowledge that methodological limitations in the studies reviewed (e.g., different methods to quantify and classify neuropathy) as well as limitations in the analysis itself (conflation of studies involving both T1DM and T2DM patients and the exclusion of relevant findings from studies that did not meet the review’s criteria) point to the need for further investigation.
Adipokines: Leptin and Adiponectin
Adipokines including leptin and adiponectin are strongly associated with T1DM. Serum levels of leptin, a hormone produced by the anterior pituitary, are positively correlated with bone mineral density but are decreased in the setting of T1DM [30, 31]. Leptin increases cortical bone but decreases trabecular bone formation. By acting on the hypothalamus, it works through the sympathetic portion of the central nervous system (CNS) to upregulate bone formation. Whereas diabetic neuropathy exerts its effects on the peripheral nervous system, leptin is more often associated with CNS-related bone metabolism; consequently other mechanisms of leptin may be relevant to DM. Leptin exerts a direct effect on bone through actions on insulin-like growth factor-1 (IGF-I) . Evidence further indicates that leptin may be the key to understanding the link between energy intake and bone metabolism .
In contrast, serum levels of adiponectin are negatively correlated with bone mineral density . T1DM is associated with increased adiponectin which is related to insulin sensitivity. Studies indicate that adiponectin is a potent insulin enhancer linking adipose tissue and glucose metabolism throughout the body  and that it may influence immune response in T1DM just as leptin affects autoimmune diabetes .
To an extent, however, the role of these adipokines remains unclear. Leptin contributes to systemic inflammatory changes and is associated with atherosclerosis, hypertension, and neointimal thickening with vascular disease . Adiponectin, which is present at lower levels in diabetic individuals, has anti-inflammatory properties , protects endothelial and vascular smooth muscle cells, and exerts a positive effect in myocardial remodeling [35, 38]. In terms of fractures, the positive effects of adipokines are countered by their negative effect on the cardiovascular system, predisposing diabetes patients to falls and increasing the risk for osteoporosis .
Glycation End Products
While the influences on both osteoblast and osteoclast formation and function significantly affect overall BMD, bone quality in individuals with DM is also reduced through several other metabolic processes. The production of advanced glycation end products (AGE) reduces levels of type 1 collagen which, in turn, increases bone flexibility. In stressful circumstances, a less rigid bone is more likely to fracture even under conditions of lower force and lower energy, such as falling or stumbling from a seated or stationary position. Table 2 summarizes the adverse effects of impaired glucose metabolism on bone.
Adverse effects of impaired glucose metabolism on bone
Factors that decrease BMD
Increased urinary calcium excretion
Poor glycemic control
Evaluate and monitor Hg A1c
Improve dietary control
Alter antidiabetic medications
Low bone turnover resulting in decreased osteoblast function (advanced T1DM)
Correct thyroid levels
Follow thyroid stimulating hormone [TSH] levels
Optimize vitamin D
Monitor renal function
Excess cortisol seen in early stages of T1DM
Optimize/supplement vitamin D and monitor serum vitamin D 25OH and parathyroid hormone [PTH] levels
Altered vitamin D metabolism
Supplement vitamin D possibly with calcitriol rather than cholecalciferol
Consider renal consultation
Adverse effects of insulin and insulin-like growth factors
Poor glycemic control that may increase need for insulin
Consider endocrine consultation
Encourage improving glycemic control through nutritional therapy
Follow growth hormone [GH] levels
Follow insulin-like growth factor-1 [IGF-1] levels
Monitor BMD, obtain levels of key pituitary hormones (gonadotropins such as follicle-stimulating hormone [FSH], luteinizing hormone [LH]; as well as growth hormone [GH] and prolactin); in addition, consider pharmacologic interventions during perimenopausal phase
A recent report by Shanbhogue and colleagues considers yet another mechanism . Comparing patients with T1DM against age-matched, healthy controls, they propose that the presence of microvascular disease may be a factor in bone loss for patients with T1DM. Specifically there were no differences between patients without microvascular disease and controls. However, T1DM patients with microvascular disease demonstrated lower total, trabecular, and cortical volumetric bone mineral density as well as microarchitectural changes in the form of thinner bone cortices at the radius, lower trabecular bone strength, and greater trabecular separation at both radius and tibia which could partially explain the higher level of skeletal fragility evident in these subjects. Differences between microvascular positive and negative T1DM remained significant after controlling for age, years of DM, and average glycated hemoglobin over the prior 3-year period. Vitamin D insufficiency and celiac disease are still other causal factors in diabetes-induced osteoporosis.
Type 1 Diabetes
Vestergaard et al. have reported a trend toward an increased fracture risk at most skeletal sites in type 1 diabetes as well as a marked trend toward higher fracture risk in the presence of complications; most of the studies examined in his analysis focused on hip fracture . For example, Nicodemus et al.  reported that postmenopausal women were 12.25 times more likely to experience a hip fracture—a finding confirmed by subsequent studies of diabetic men and women in the relevant age groups  and in a different study, specifically in women ages 34–59 . A recent study by Weber et al.  was the first to report that an increase in fracture risk begins in childhood and adolescence and extends over the life span of T1DM patients. Men ages 60–69 and women ages 40–49 have double the fracture risk of those without diabetes. Moreover, people with retinopathy and neuropathy have a higher fracture risk in the lower extremities with falls being a major contributing factor.
Type 2 Diabetes
In recent years, increased fracture risk, formerly associated primarily with T1DM, has become a growing concern in T2DM patients, although they are still affected to a lesser degree. In terms of hip fractures, Nicodemus et al. found a 1.7-fold increased risk of hip fractures in postmenopausal women with T2DM than in those without diabetes . An association between higher fracture incidence and such factors as longer disease duration, decreased bone quality, diabetic complications, inadequate glycemic control, the use of insulin or oral diabetes medications, and increased fall risk has also been identified and reported. Despite the paradox of higher bone density coexistent with increased fracture risk in T2DM, Schwartz et al. determined  that women ages 65 and older were at greater risk of developing hip, proximal humerus, and foot fractures than nondiabetic women, in part because of associated comorbidities including decreased bone quality and impaired balance and gait due to neuropathy, and visual impairment resulting from diabetic retinopathy and cataracts.
The recognition that diabetes compromises bone health, particularly in an aging population, strengthens the need to incorporate bone assessment together with possible treatment options as an integral part of long-term diabetes care. A 2015 International Osteoporosis Foundation review of bone fragility in T1DM  strongly recommends early and regular evaluation of fracture risk in T1DM coupled with the implementation of fracture prevention strategies; in addition, it advocates intensified efforts to evaluate the efficacy of anti-osteoporotic agents in the context of diabetes.
Complications of Diabetes Mellitus Related to Bone and Physical Function
Diabetes mellitus and its neuropathies are regarded as the most common cause of Charcot osteoarthropathy (COA), also known as Charcot foot. A chronic, progressive, potentially limb-threatening disease, it is relatively rare, occurring in an estimated 0.08–7.5 % of patients with both T1DM and T2DM . Characterized by destruction of bone and joint integrity, it initially presents with redness, swelling, and increased warmth, progressing to severe deformities including collapse of the midfoot and ulcers that could predispose to amputation.
COA is associated with vascular calcification which includes abnormal calcified deposits in the smooth muscle of blood vessels of all sizes and with atherosclerosis that results in vascular stiffness and increases systolic blood pressure . The primary underlying etiology of the disease is thought to be increased trauma resulting from impaired sensory feedback of the joint under conditions of both peripheral and autonomic neuropathy. This trauma, often minimal in nature, causes excess production of pro-inflammatory cytokines including TNF-α which, in turn, leads to an increase in RANKL-mediated osteoclast activation, causing bone fracture and destruction [47, 48].
The first step in treating COA is to control the heat and swelling and stabilize the foot to prevent disease progression and minimize deformity. Nonoperative treatment generally includes the use of a total contact cast or a bivalved cast (Aircast walker) followed by bracing and the use of footwear designed to accommodate preexisting deformities, relieve pressure, and ensure joint stability . Surgical treatment, reserved for patients with recurrent joint instability and ulceration, may entail removal of a bony prominence, midfoot fusion, and realignment osteotomy. Pharmacological therapies including bisphosphonates and calcitonin as well as anabolic agents such as human parathyroid hormones are being investigated as treatment options with some early success .
Diabetes Medications Detrimental to Bone
The link between fracture risk and diabetes medication is most clearly established in the class of drugs called thiazolidinediones (rosiglitazone/Avandia and pioglitazone/Actos). Although their efficacy in controlling diabetic hyperglycemia has been demonstrated, their prolonged use negatively impacts osteoblastogenesis by decreasing activity of both osteoblast transcription factors (e.g., RUNX2) and osteoblast signaling pathways (e.g., ICF-1) . As a result, thiazolidinediones decrease bone formation and bone mineral density while increasing bone reabsorption, leading to greater fracture risk. A large, population-based case–control analysis demonstrated that the use of rosiglitazone and pioglitazone in men and women with T2DM for 12 or more months may be linked to a two to threefold increased risk of hip and nonvertebral osteoporotic fractures . Both drugs are now in limited use as a result of FDA warnings about the adverse heart-related side effects of rosiglitazone and the heightened risk of bladder cancer of pioglitazone .
Recently, canagliflozin (Invokana, Invokamet), a sodium–glucose cotransporter-2 (SGLT2), has been used in combination with a sulfoylurea, pioglitazone, or short acting insulins to lower blood sugar in T2DM by stimulating the kidneys to remove sugar through the urine. In 2015 the FDA issued two warnings regarding the use of canagliflozin, one dealing with bone fracture risk and decreased BMD  and the other with the presence of too much acid in the blood (acidosis) due to the production of high levels of ketones . Drawing on the results of several clinical trials, the first warning was based on findings that fractures occur more frequently with canagliflozin than with placebos and within a time span of 12 weeks after initiating treatment. It is not FDA approved for patients with T1DM.
Antiepileptic medications such as gabapentin and pregabalin are commonly used as therapy for the pain associated with diabetic peripheral polyneuropathy. As a class, they affect balance and coordination, increasing fall and fracture risk; moreover, they also lead to vitamin D25(OH) insufficiency and deficiency . Large-scale RCTs as well as long-term follow-ups are needed to elucidate the efficacy of antiepileptic drugs in neuropathic pain . Patients with diabetic polyneuropathy may also receive selective serotonin–norepinephrine reuptake inhibitors (SNRIs), a class of antidepressant medications that is associated with decreased bone mineral density, increased falls, and a greater risk of nonspine fracture including hip fractures .
Prevention and Treatment of Diabetes Mellitus-Related Bone Disease
Treatment of bone disease in diabetes requires a multipronged approach. Several of the following therapies apply to osteoporosis in general. Others are related to conditions specific to diabetes.
The first step is to minimize any inciting events that adversely affect bone demineralization and increase fracture risk including poor glycemic control, harmful medications, and falls. Patients with T1DM are at particularly high risk of osteoporotic fractures, with T2DM patients affected to a lesser degree; however, both groups of patients should be made aware of the principal causes of osteoporosis in diabetes, particularly insulin deficiency and the impact of peripheral neuropathy and retinopathy. As Brown et al. emphasize, no osteoporosis screening recommendations have been adopted for patients with diabetes, but it is deemed prudent to provide screening for both men and women (particularly thin women), with T1DM complications . In T2DM, conventional dual-emission x-ray absorptiometry scans may be misleading given that, in this condition, higher BMD coexists with increased fracture risk due primarily to falls .
Poor nutrition and a compromised lifestyle are factors contributing to the development of osteoporosis in diabetes. Diets with adequate amounts of calcium and vitamin D or supplements if needed should be maintained in order to help ensure bone health and optimal glucose control. Smoking and excessive alcohol intake should be avoided. Weight management is an issue for both excessively thin women with T1DM and obese and overweight women with T2DM. Risk factors for falls including advanced age, household hazards, and impaired balance should also be minimized (Table 3).
Factors that increase falls in diabetic patients
Altered sensation and proprioception and balance
Foot ulcers that alter weight-bearing
Use of assistive devices (cane, walker) if appropriate
Improve glucose control
Diabetic retinopathy and cataracts
Retinal vascular changes that impair visual acuity caused by years of poor glucose control
Routine optical evaluation
New medications, excessive doses of antihypertensive medications, or dehydration
Educate patient on getting up from seated position
Avoid drastic dose alternations in antihypertensive medications
May cause syncope or dizziness
Close monitoring of glucose levels throughout day
The next factor in both prevention of further decline and ongoing treatment is regular physical therapy to develop proprioceptive and balance skills and to increase and maintain bone and muscle strength. With the assistance of a physical therapist, if needed, diabetic patients should be encouraged to walk, jog, dance as well as practice yoga and engage in weight-bearing and resistance exercises. As predicated in Wolff’s law (bone adapts to the loads placed upon it), bone strength is directly correlated with use. Given painful peripheral polyneuropathy, retinopathy, and poor proprioception as well as possible cardiac deconditioning and a propensity for coronary vascular accidents, diabetic patients experience a decline in activity. In contrast, maintaining appropriate activity levels not only contributes to healthy bone remodeling as well as muscle coordination and balance, but it also exerts beneficial effects on glycemic control, atherosclerosis risk, and weight control .
A number of medications that positively alter the bone formation and reabsorption balance have proved effective in treating diabetic osteoporosis. In the first instance, recombinant insulin therapy, acting through its osteoblast receptors, exerts an osteogenic effect on osteoblasts . As Gopalakrishnan et al.  have shown, insulin in combination with estradiol counters the deleterious effect of high concentrations of glucose on osteoblast proliferation and function.
The antidiabetic drug, metformin, positively influences bone turnover and is associated with a decrease in risk fracture. It not only has a direct osteogenic effect at all glucose concentrations  but in animal studies, it has been shown to exert a positive impact on osteoblast differentiation and function both in vivo and in vitro . Long used in T2DM, metformin has recently assumed new importance as the focus of a proposed study examining its efficacy in treating several age-related ailments including cardiovascular disease, cancer, and cognitive impairment—a significant departure from studies addressing treatments for only a single disease .
A study of ovariectomized and non-ovariectomized rats demonstrates that glimepiride, a first-line drug in the treatment of T2DM, inhibits the deleterious bone changes caused by estrogen deficiency in ovariectomized rats and heightens bone formation, indicating that it may reduce the risk of osteoporosis, particularly in postmenopausal women .
In terms of prescription agents for osteoporosis, the bisphosphonates—specifically alendronate, risedronate, and pamidronate—have become a significant addition to the therapeutic armamentarium for osteoporosis. By reducing osteoclast activity, they inhibit bone resorption, thereby preventing bone loss and inducing increased BMD. Interestingly, recent studies have indicated a possible correlation between the use of alendronate and both a decrease in daily insulin requirements as well as a possible decrease in T2DM itself. As a treatment for senile T1DM alendronate produced an increase in BMD accompanied by a reduction in the required daily consumption of insulin, perhaps because it alleviated some of the pain, rigidity, and restricted movement in osteoporosis, enabling patients to improve their physical activity .
An examination of the use of alendronate in patients with T2DM revealed a reduced risk of T2DM in users of alendronate as opposed to a 21 % increased risk of developing the disease in those not receiving the drug. Increased physical activity may also be a factor in this analysis . Similarly, a British study found that the long-term use of bisphosphonates reduced the chance of developing T2DM by one-half with a greater risk reduction in women (51 %) than in men (23 %); a slight increase in risk occurred in the period from 1 to 2.5 years of exposure, followed by a sustained decrease thereafter . These findings await confirmation. Few if any bisphosphonate treatments have been studied in patients with both diabetes and osteoporosis, although small studies have shown the efficacy of pamidronate in COA .
Compared with bisphosphonates, the selective estrogen receptor modulator, raloxifene, exhibits relatively modest BMD gains but causes reductions in vertebral fractures similar to those of bisphosphonates. A randomized clinical trial involving 40 postmenopausal women with T2DM found that raloxifene did not affect either glycemic control or insulin sensitivity . Although approved by the FDA for treatment of postmenopausal women with osteoporosis, the androgynous peptide, calcitonin, is regarded as a second-tier therapy because of the availability of more effective drugs, the lack of definitive evidence on calcitonin’s efficacy in preventing fracture, and recent studies indicating a possible causal relationship with cancer .
Also approved by the FDA but with a 2-year limitation, parathyroid hormone (PTH) is generally reserved for patients at greatest risk of fracture, not only because of its cost but also because of its possible relation to increased risk of osteosarcoma . This risk has only been observed in laboratory animals, but individuals with high-risk conditions such as Paget’s disease of the bone or prior radiation should avoid PTH .
The protein PPAR-γ, currently the focus of efforts to develop insulin sensitivity in T2DM, shows highly preliminary but promising results as a new therapeutic approach to bone formation. PPAR-γ is known to inhibit the production of stem cells in bone marrow, preventing the cells from developing into bone, cartilage, and connective tissue. In a laboratory trial involving mice and human tissue, Marciano et al. found that when stem cells were treated with a compound that represses PPAR-γ activity, a statistically significant increase occurred in osteoclast formation leading to increased bone formation. The next step is to test the compound in animal models of bone loss, aging, obesity, and diabetes . These and other investigations related to PPAR-γ, together with the development of new medications, are forthcoming.
Critical Illness Polyneuropathy and Polymyopathy
Critical illness polyneuropathy (CIP), particularly when associated with sepsis and systematic inflammatory response syndrome (SIRS), is one of the most common neuromuscular complications of critical illness. An axonal degenerative polyneuropathy presenting as both limb and respiratory muscle weakness, CIP affects primarily distal motor fibers as opposed to proximal ones . It is often cited as an underlying factor in a patient’s difficulty in weaning from a mechanical ventilator, thereby increasing the risk of intensive care morbidity; greater susceptibility to infection and organ failure are also likely to result . CIP and an overlapping syndrome, critical illness myopathy (CIM), are thought to occur in approximately 25–50 % of patients admitted to the intensive care unit with SIRS or sepsis .
The etiology of critical illness polyneuropathy is unclear. Observations of its clinical course have led to speculation that it may be caused by a defect in the transportation of nutrients through the axon—a process that requires significant energy expenditure which may be deficient due to the sepsis and various interleukins and cytokines that affect cellular respiration. Further, microcirculation to peripheral nerves may be impaired by sepsis and its cardiovascular consequences as well as by elevated glucose levels associated with diabetic polyneuropathy .
In terms of diagnosis, the following criteria for critical illness polyneuropathy have been put forward by Latronico and Bolton :
Patient is critically ill with multi-organ dysfunction.
Patient has limb weakness or difficulty in weaning after non-neuromuscular etiologies have been ruled out.
Electrophysiological evidence of axonal motor and sensory polyneuropathy exists.
Detrimental response on repetitive nerve stimulation is absent, thus excluding neuromuscular junction pathology.
A diagnosis of CIP is established if all four of these criteria are met. In the absence of limb weakness or difficulty in weaning from a ventilator but in the presence of other criteria, critical illness polyneuropathy is considered probable but cannot be confirmed.
Medical care for CIP emphasizes intensive insulin treatment (IIT), early mobilization through physiotherapy, and electrical muscle stimulation. Studies indicate that CIP and its accompanying hyperglycemia may be mitigated with strict glucose control . A 2001 RCT enrolling 1,548 surgical ICU patients demonstrated that IIT to maintain blood glucose level at or below 110 mg per deciliters reduced overall in-hospital mortality by 34 % and CIP by 44 %, with patients less likely to require prolonged mechanical ventilation and intensive care . On the basis of these results, IIT was widely prescribed. However, a subsequent 2009 trial involving 3,054 patients on IIT and 3,054 on conventional glucose control reported that IIT increased the absolute risk of death at 90 days by 2.6 % and recommended that a blood glucose level of 180 mg or less per deciliter be adopted. IIT is also known to increase the risk of hypoglycemia .