CATHERINE BARRET PGY4 SEPTEMBER 17, 2014 MUSCULOSKELETAL COMPLICATIONS IN DIABETES.

CATHERINE BARRET PGY4 SEPTEMBER 17, 2014 MUSCULOSKELETAL COMPLICATIONS IN DIABETES

DIABETES COMPLICATIONS: MUSKULOSKELTAL COMPLICATIONS!

OBJECTIVES General overview of the different musculoskeletal (MSK) complications associated with diabetes Review the recent results from the DCCT/EDIC trial on MSK complications amongst patients with type 1 diabetes Review clinical manifestations, pathophysiology and treatment of neuropathic osteoarthropathy Discuss the increased risk of fractures amongst diabetic patients and the proposed mechanisms in type 1 and type 2 diabetes

HANDSHOULDERLOWER LIMBSPINE Limited joint mobility Dupuytrens contracture Flexor tenosynovitis Carpal tunnel syndrome OA Adhesive capsulitis Limited joint mobility Basic calcium phosphate deposition disease Diabetic muscle infarction Neuropathic arthropathy Osteoarthritis Gout, pseudogout, OA Diffuse Idiopathic skeletal hyperostosis OA

DIABETIC CHEIROARTHROPATHY Limited joint mobility Thick, tight, waxy skin mainly over the dorsal aspect of MTP and IP joints of hands Painless May lead to flexion contractures LJM in the foot (MTP and subtalar joints) may risk of foot ulceration 30-58% of patients with DM1 and 45-67% with DM2 compared to 4-20% of patients without DM Prevalence increases with age and cigarette smoking in both diabetics and non-diabetics Associated with HgA1C and duration of diabetes Clin Rheumatol (2013) 32:527533

DIABETIC CHEIROARTHROPATHY PATHOPHYSIOLOGY: glycosylation of collagen in skin and periarticular tissues collagen degradation Diabetic microangiopathy Diabetic neuropathy Clin Rheumatol (2013) 32:527533

DIABETIC CHEIROARTHROPATHY DIAGNOSIS: Prayer sign: Inability to oppose the palmer surfaces of hands and fingers with the wrists dorsiflexed Table top sign: inability to make contact with the entire surface of the palm and fingers on a flat surface when laying their palms on a table top with the fingers spread out Clin Rheumatol (2013) 32:527533

DIABETIC CHEIROARTHROPATHY TREATMENT: Physiotherapy to increase range of motion and improve strength Optimize glycemic control Encourage smoking cessation Clin Rheumatol (2013) 32:527533

DUPUYTRENS CONTRACTURE Prevalence in DM 16-42% compared with 13% of the general population with age and duration of DM and equally affected Middle and ring finger more common 13-39% of patients with Duputyrens contracture will have DM when evaluated Palmer or digital thickening, tethering, pretendinous bands & flexion contractures in the fingers Clin Rheumatol (2013) 32:527533

DUPUYTRENS CONTRACTURE PATHOPHYSIOLOGY: Genetic predisposition (Wnt signaling pathway) Trauma, long term hyperglycemia, microangiopathy, and ischemia resulting in production of oxygen free radicals TREATMENT: Glycemic control Physiotherapy, occupational therapy Injections of collagenase Clostridium histolyticum Reduces fixed flexion contractures and improves joint ROM Adverse events: tendon rupture, complex regional pain syndrome Surgery if hand function is severely affected Clin Rheumatol (2013) 32:527533

FLEXOR TENOSYNOVITIS Trigger finger Fibrous tissue proliferation in the tendon sheath leading to limitation and restriction of tendon movement Prevalence in DM 11% vs1% of the general population DM patients may have multiple digits involved Commonly involves the thumb, middle and ring fingers Correlates with duration of DM but not with glycemic control Clin Rheumatol (2013) 32:527533

FLEXOR TENOSYNOVITIS TREATMENT Activity modification NSAID Splinting Corticosteroid injection into the tendon sheath Surgical release Clin Rheumatol (2013) 32:527533

CARPAL TUNNEL SYNDROME PREVALENCE: 14% of DM patients without diabetic polyneuropathies Up to 30% of DM patients with polyneuropathies prevalence associated with the duration of DM 3.8% of the general population Median nerve distribution Clin Rheumatol (2013) 32:527533, www.uptodate.com Entrapment neuropathy of the median nerve

CARPAL TUNNEL SYNDROME CLINICAL MANIFESTATIONS Pain, tingling and paresthesia in the distribution of the median nerve Thumb, index finger, middle fingers and radial aspect of the ring finger Symptoms may improve by shaking or flicking the wrist (flick sign) Symptoms worse at night Bilateral CTS common but symptoms may not occur simultaneously in both hands grip strength and function may occur

CARPAL TUNNEL SYNDROME PATHOPHSYIOLOGY: Accumulation of glycation end products Intrinsic nerve factor pathology secondary to: Microagniopathy Macrophage dysfunction Abnormalities in the retrograde cell body reaction Schwann cell dysfunction Decreased expression of neurotrophic factors and their receptors

Clin Rheumatol (2013) 32:527533, www.uptodate.com

CARPAL TUNNEL SYNDROME Nerve conduction studies Imaging US: thickening of the median nerve, flattening of the median nerve within the tunnel and bowing of the flexor retinaculum (sensitivity 65.7%) MRI: swelling of the median nerve and increased signal intensity on T2 weighted images (sensitivity 96%, specificity 33-38%) TREATMENT: Splinting Corticosteroid injection NSAIDs Surgery Clin Rheumatol (2013) 32:527533

ADHESIVE CAPSULITIS OF THE SHOULDER Frozen shoulder Progressive painful restriction of shoulder movements especially external rotation and abduction (active and passive) Three phases: Pain Adhesion Recovery Clin Rheumatol (2013) 32:527533

ADHESIVE CAPSULITIS OF THE SHOULDER 10-29% of DM compared to 3-5% of the general population Amongst patients with adhesive capsulitis there is an increased prevalence of prediabetes and diabetes Occurs at a younger age, is less painful, lasts longer and responds less well to treatment Bilateral involvement more common (33-42% vs 5-20%) Linked to disease duration and other complications Limited joint mobility, autonomic neuropathy (DM1 and DM2) and MI (DM1) Clin Rheumatol (2013) 32:527533

ADHESIVE CAPSULITIS OF THE SHOULDER PATHOPHYSIOLOGY: Excessive glucose concentration leads to a faster rate of collagen glycosylation and cross-linking in the shoulder capsule, restricting range of motion CLINICAL MANIFESTATIONS: Painful phase: diffuse, severe and disabling shoulder pain worse at night with increasing stiffness. Intermediate phase: stiffness and severe loss of shoulder motion. Pain becomes gradually less pronounced. Recovery phase: gradual return of ROM. Clin Rheumatol (2013) 32:527533

Affected Shoulder Unaffected Shoulder External Rotation Abduction Internal Rotation www.uptodate.com

ADHESIVE CAPSULITIS OF THE SHOULDER DIAGNOSIS: Limited ROM (active and passive) in at least two planes of movement Pain persists despite anesthetic injection in the subacromial space Xray: normal, may show osteopenia MRI and US useful in eliminating other causes of a painful shoulder TREATMENT: Analgesia IA corticosteroid injections Graded exercise program Surgery (refractory cases)

MUSCULOSKELETAL COMPLICATIONS AND THE DDCT/EDIC TRIAL

MUSKULOSKELETAL COMPLICATIONS AND THE DDCT/EDIC TRIAL PURPOSE: Describe the prevalence of cheiroarthropathy in the DCCT/EDIC cohort Examine the effect of intensive vs conventional therapy on cheiroarthropathy Identify predisposing risk factors for cheiroarthropathy Cheiroarthropathy includes adhesive capsulitis, carpal tunnel syndrome, tennosynovitis, dupuytrens contractures or a positive prayer sign

DDCT/EDIC TRIAL DCCT: 1983-1993 1441 subjects aged 13-39 years, duration of DM 1-15 years Intensive vs conventional therapy Two cohorts: Primary prevention: DM1 1-5 years, no retinopathy and urinary albumin excretion

DDCT/EDIC TRIAL Annual EDIC assessment Disabilities of the arm, shoulder and hand (DASH) questionnaire Examined for: Prayer sign Finger extension Bilateral shoulder flexion HgA1C and lipids Collagen glycation measured as skin autofluorescence using a spectrometer

DDCT/EDIC TRIAL Average age was 52 years Mean duration of DM was 31 years Cheiroarthropathy present in 807 ( 66% ) of subjects Adhesive capsulitis 31% Flexor tenosynovitis 28% Positive prayer sign 22% Dupuytrens contracture 9% Most common combinations: Carpal tunnel syndrome + flexor tenosynovitis Carpal tunnel syndrome + adhesive capsulitis

Diabetes Care 2014;37:1863-1869

Association of prevalence of cheiroarthropathy by tertiles of time-weighted HgA1C during the DCCT/EDIC (1983-2011)

The associated between cheiroarthropathy and age, sex, duration of diabetes or HgA1C remained significant after adjustment for retinopathy, neuropathy and nephropathy. The association with neuropathy remained significant in a multivariable model adjusting for other risk factors, whereas the association with retinopathy remained nominally significant (P = 0.0547). Odds Ratio for neuropathy 1.60, nephropathy 0.85 and retinopathy 1.45 after adjustment for age, sex, duration of diabetes and time weight HbA1C. Diabetes Care 2014;37:1863-1869

DCCT/EDIC SUMMARY Cheiroarthropathy was present in 66% of subjects and was associated with age, duration of diabetes, glycemic control, female gender, neuropathy and retinopathy There was no difference between the prevalence of cheiroarthropathy amongst patients of the intensive group (64%) vs the conventional group (68%)

OTHER MSK COMPLICATIONS

DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS (DISH) Diffuse calcification and ossification of the ligaments and enthuses 13-40% of patients with type II DM compared to 2.2- 3.5% of the general population Prevalence of the metabolic syndrome is higher amongst DISH patients The spine is the most affected and can cause spinal rigidity & impingement of nearby structures & nerves Can occur in extrapsinal sites with prominent bony reactions at ligament and tendon insertion sites Pelvis, greater trochanters, patellae and calcaneus Clin Rheumatol (2013) 32:527533

DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS PATHOGENESIS: Exact mechanism is unknown Insulin, growth hormone and IGF1 are proposed factors that promote bone growth in DISH Atherosclerosis damaged endothelium and aggregation of platelets increased levels of IGF1 and osteoblast proliferation increased bone formation Clin Rheumatol (2013) 32:527533

DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS DIAGNOSIS: Resnick and Niwayamas 1976 criteria: Flowing ligamentous calcifications involving at least four contiguous vertebral bodies Preservation of interveretebral disk space Absence of changes of degenerative spondylosis or spondylarthropathy TREATMENT: Analgesia Surgery limited to impinging bone bridges when critical functions are compromised

MUSCLE INFARCTION Rare complication Longstanding poorly controlled DM Retinopathy, nephropathy or neuropathy Thigh muscles commonly involved but the calf, upper extremities and abdominal wall muscles have all been reported Acute pain with swelling in an extremity Persists at rest and worsens with exercise Palpable mass in 34-44% No history of trauma

MUSCLE INFARCTION PATHOGENESIS: Arteriosclerosis Diabetic microangiopathy Hypercoagulability Endothelial dysfunction DIAGNOSIS: CK n/ MRI: diffuse edema and swelling Muscle biopsy (rare): muscle necrosis and edema, phagocytosis of necrotic muscle fibers, granulation tissue and collagen deposition

MUSCLE INFARCTION TREATMENT: Bed rest Analgesia Glycemic control Most patients recover spontaneously over weeks- months of bed rest Recurrence rate in the same or contralateral extremity is ~ 40%

GOUT Monosodium urate crystal deposition disease Prevalence of the metabolic syndrome is high among patients with hyperuricemia or gout Obesity associated with purine and/or urate overproduction Hyperuricemia is an independent risk factor for the development of DM Clin Rheumatol (2013) 32:527533 Needle shaped, negatively birefringent crystals

GOUT Acute: Recurrent attacks of arthritis Severe pain, redness, warmth, swelling and disability Maximum severity reached within 12 to 24 hours 80% of initial attacks involve a single joint (1 st MTP or knee) Signs of inflammation often extends beyond the joint and can mimic dactylitis or cellulitis Chronic: Tophaceous gout Tophi usually not painful Attenuate the skin revealing a yellow or white color May become inflamed DDX: septic arthritis, trauma, CPPD

GOUT TREATMENT: Acute Flare NSAIDs Naproxen 500mg BID or Indomethacin 50mg TID Contraindicated in moderate-severe CKD (CrCl < 60), active PUD, heart failure, allergy Colchicine Diminished benefit for attacks > 72-96 hours 1.8mg in divided doses on day 1 followed by 0.6mg OD-BID Dose reduction necessary in CKD Contraindicated in advanced CKD or hepatic impairment Multiple drug interactions Steroids Intraarticular, oral Lifestyle modification Uric acid lowering therapy

CALCIUM PYROPHOSPHATE DIHYDRATE CRYSTAL DEPOSITION DISEASE Calcium pyrophosphate dihydrate crystal deposition DM is a possible risk factor Frequently asymptomatic Can mimic other types of arthritis Pseudogout (acute CPP crystal arthritis) Knees, wrist and MCP joints Pseudo-rheumatoid arthritis (chronic CPP crystal inflamamtory arthritis) Pseudo-osteoarthritis Pseudo-neuropathic joint disease Clin Rheumatol (2013) 32:527533

CALCIUM PYROPHOSPHATE DIHYDRATE CRYSTAL DEPOSITION DISEASE Rhomboid, weakly positively birefringent CPPD crystals Chondrocalcinosis on xray Punctate and linear radiodensities in cartilage Less commonly appear in ligaments and joint capsules www.uptodate.com

CALCIUM PYROPHOSPHATE DIHYDRATE CRYSTAL DEPOSITION DISEASE TREATMENT: Acute attacks of pseudogout: NSAIDs Colchicine Intra-articular/PO steroid

OSTEOARTHRITIS Obesity is a risk factor for OA Peripheral neuropathy may the risk of advanced, aggressive OA In cultured human articular cartilage, AGE levels resulted in stiffness of the collagen network maintenance and repair capacity of human articular cartilage Clin Rheumatol (2013) 32:527533

BASIC CALCIUM PHOSPHATE CRYSTAL DEPOSITION DISEASE Intra-articular and periarticular structures CPPD crystals frequently coexist Calcific tendonitis or calcific periathritis Tendonitis Bursitis Enthesitis OA or large joint destructive arthritis (less common) Shoulder (most common), greater trochanters, elbows, wrists and digits 31.8% of DM patients will have shoulder calcifications vs 10% of controls Clin Rheumatol (2013) 32:527533

BASIC CALCIUM PHOSPHATE CRYSTAL DEPOSITION DISEASE DIANGOSIS; Intra-and/or peri-articular calcifications +/- erosions, destructive or hypertrophic changes Crystals are small, not birefringent and can be mistaken for dirt or debris TREATMENT: Analgesia Joint aspiration +/- glucocorticoid Surgery

REFLEX SYMPATHETIC DYSTROPHY Complex regional pain syndrome Localized or diffuse pain in the upper or lower extremity associated with swelling, vasomotor disturbances and trophic skin changes (hair loss, skin color changes, temperature changes and skin thickening) DM patients may predisposed to RSD TREATMENT: Analgesics Physiotherapy IV bisphosphonates Calcitonin Oral corticosteroids Sympathetic ganglion blocks Clin Rheumatol (2013) 32:527533

NEUROPATHIC OSTEOARTHROPATHY

Charcot osteoarthropathy Progressive destructive process affecting the bone and joint structure leading to subluxation, dislocation, deformity and ulceration of the foot and ankle joints DM is the most common etiology Prevalence in DM is 0.08% to 7.5% Duration of diabetes > 10 years J of foot and ankle surgery (2013) 740-749, Clin Rheumatol (2013) 32:527533

NEUROPATHIC OSTEOARTHROPATHY PATHOGENESIS: Neurotraumatic theory: repeated trauma in the setting of decreased sensation leading to increased damage with microfractures Neurovascular theory: autonomic neuropathy (sympathetic denervation) increases blood flow into bone resulting in stimulation of osteoclasts with increased bone resorption, osteoporosis, fractures and joint damage Uncontrolled inflammation is the final common pathway and leads to an osteoclast-osteoblast imbalance RANKL dependent and independent pathways increased osteoclast activity Clin Rheumatol (2013) 32:527533

NEUROPATHIC OSTEOARTHROPATHY NATURAL HISTORY: Acute phase Foot is warm, edematous and erythematous Pain depends on degree of neuropathy Chronic phase Bone fragments are resorbed, edema decreases and the foot starts to heal. Deformity of the foot with abnormal pressure on the planter surface due to collapse of the plantar arch and the development of a rocker bottom deformity Collapsed and destroyed ankle joints in hind-foot Charcot Calluses may form which are liable to ulcerations especially in the mid-foot Clin Rheumatol (2013) 32:527533

J of foot and ankle surgery (2013) 740-749

NEUROPATHIC OSTEOARTHROPATHY CLINICAL FEATURES: High index of suspicion Swelling, redness and pain (sometimes) in the foot of short duration (4-6 weeks) Subluxation and foot deformity may be present Systemic features of infection should be absent Peripheral pulses are usually palpable DDX: cellulitis, DVT or acute gout

NEUROPATHIC OSTEOARTHROPATHY DIAGNOSIS: Plain radiographs are not very useful in the acute phase Chronic changes include subchondral sclerosis, osteophytosis, intra-articular loose bodies, subluxation, dislocation of the midtarsal bones and bone resorption MRI may show bone marrow edema, bone bruising or microfractures Bone scans will identify pathologic features within bone but are not specific for osteoarthropathy Clin Rheumatol (2013) 32:527533

NEUROPATHIC OSTEOARTHROPATHY TREATMENT: Non weight bearing x 3 months Bisphosphonates have been used but there is a lack of conclusive evidence for treating the active Charcot foot Surgery

OSTEOPOROSIS

Both T1DM and T2DM are associated with an increased risk of fracture of the hip, proximal humerus, foot and all non vertebral fractures In both types of DM, bone quality and strength are diminished Jackuliak et al. 2014 Curr Diab Rep (2013) 13:411418,

Risk factors for osteoporotic fractures in DM Jackuliak et al. 2014

OSTEOPOROSIS Bone mineral density is decreased in T1DM Children: average BMD is 0.5-1.5 standard deviations below the mean (z score) Adolescent boys: 10% deficit in bone mineral content Adolescent girls: 5% deficit in bone mineral content Independent of HgA1C Adults: studies are less clear gonadal function may play a role No correlation between BMD and HgA1C, DM duration or age of onset Correlation between BMD and HgA1C in patients with retinopathy Curr Diab Rep (2013) 13:411418

OSTEOPOROSIS Bone mineral density is increased in TIIDM trabecular bone with cortical bone BMI plays a role in BMD determination

OSTEOPOROSIS HYPERGLYCEMIA: Relationship with fracture risk is NOT linear Gene expression associated with OB maturation in DM1 mice is suppressed by acute and chronic hyperglycemia PPARy expression increases formation of adipocytes at the expense of OB formation production IL-6 from osteoblasts (OB) stimulates OC to resorb bone Poor glycemic control impairs the response of OB and OC to 1,25(OH)2 vitamin D in type II DM markers of bone formation (osteocalcin) with normal resorption markers (N-telopeptide) Advanced glycation end products in collagen leads to inferior bone quality and strength urinary calcium excretion and functional hypoparathyroidism especially in T1DM Jackuliak et al. 2014

OSTEOPOROSIS OSTEOCALCIN: Osteocalcin is a hormone secreted by the OB Activation of insulin receptor in OB induces osteocalcin production which beta cell proliferation, insulin secretion, insulin sensitivity and energy expenditure Osteocalcin targets testes to regulate testosterone production in Leydig cells In postmenopauseal , osteocalcin was associated with bood glucose, waist circumference and presence of T2DM Front. Med. 2013, 7(1): 8190

Hamman et al: Nature Reviews Endocrinology 2012;8:297-305

OSTEOPOROSIS HYPOGLYCEMIA: Low A1C has been associated with increased falls in the setting of insulin therapy Higher incidence of fractures in patients on insulin ACCORD did not show any association with intense glycemic control and falls or fractures Jackuliak et al. 2014

OSTEOPOROSIS INSULIN: Insulin deficiency is associated with abnormalities in GH/IGF- 1/IGFBP-3 pathway: GH secretion circulating IGF-1 and IGF Binding Protein 3 (IGFBP-3) These abnormalities are also associated with the presence of retinopathy, nephropathy and neuropathy Insulin receptors are present on bone in rodent and in vitro studies. Insulin receptor substrates (IRS1 and IRS2) essential for insulin/IGF-1 signaling Insulin stimulates OB with bone formation markers, promotes collagen synthesis and increases glucose uptake Observational studies in humans suggest that DM women not on insulin have an increased hip fracture risk compared with age-, BMI-matched and non-diabetic controls DM women on insulin have an risk of foot fractures Maturitas 2013(76):253-9

OSTEOPOROSIS TZDs: Peroxisome proliferator activated receptor (PPAR y) agonists Found throughout the body including bone risk of hip and wrist fracture BMD among pre & post menopausal and older Preferential differentiation of stem cells into adipocytes at the expense of OB formation in the bone marrow bone formation markers (alkaline phosphatase and procollagen type 1 N terminal propeptide) return to normal after the first 12 months of treatment. Impede androgen production which also leads to adipocyte production in the bone marrow Maturitas 2013(76):253-9

OSTEOPOROSIS METFORMIN: Enhanced OB differentiation, inhibited OC differentiation, prevented bone loss and increased BMD in rats without ovaries SULFONYLUREA: Decreased vertebral fractures in postmenopauseal DPP4 & GLP-1: ? Increased BMD, ? Decreased AGEs Hamann et al. Nature Rev Endocrine 2012;8:297-305, Maturitas 2013(76):253-9

Maturitas 2013(76):253-9

Jackuliak et al. 2014

Vestergaard et al Calcif. Tissue Int. 2011;88:209-214, Hamman et al: Nature Reviews Endocrinology 2012;8:297-305 Alendronate prospectively evaluated in T2DM and lead to improvements in BMD at hip and lumbar spine. Retrospective studies have determined effectiveness of fracture prevention with Alendronate, Clodronate, Etidronate and Raloxifene in diabetic patients.

OSTEOPOROSIS SUMMARY: Both TIDM and TIIDM are associated with fracture risk BMD does not fully explain fracture risk in T1DM in T2DM Bone quality and strength diminished in both types Potential for increased risk of falls secondary to hypoglycemia, retinopathy and neuropathy Current fracture assessment tools do not incorporate DM as a risk factor and may underestimate fracture risk

SUMMARY Certain musculoskeletal disorders are more common amongst patients with diabetes. Advanced glycation end-products, microangiopathy and neuropathy are implicated in the pathogenesis of many of these complications. The duration of diabetes and glycemic control may increase a patients risk for the development of musculoskeletal complications. More studies are needed to determine whether intervention with tighter glycemic control prevents development of cheiroarthropathy

REFERENCES Al-Homood. Rheumatic conditions in patients with diabetes mellitus. Clin Rheumatol. 2013(32):527-533 Antanopoulou M. Diabetes and bone health. Maturitas. 2013(76):253-9. Jackuliak P and Payer J. Osteoporosis, fractures and diabetes. Int J of endocinology. 2014. Hamann C, Kirschner S et al. Bone, sweet bone osteoporotic fractures in diabetes mellitus. Nat Rev Endocrinol. 2012(8):297-305. Larkin MA, Barnie A et al. Musculoskeletal complications in type 1 diabetes. Diabetes Care. 2014:1863-1869. Sealand R et al. Diabetes mellitus and osteoporosis. Curr diab Rep 2013(13):411-8. www.uptodate.com Varma A. Charcot neuroarthropathy of the foot and ankle: A Review. The journal of foot and ankle surgery. 2013:740-749. Vestegaard P, Reinmark L et al. Are antiresorptive drugs effective against fractures in patients with diabetes? Calci Tissue Int. 2011(88):209-14. Yan W and Li X. Impact od diabetes and its treatments on skeletal diseases. Front Med. 2013(7):81-90.

CATHERINE BARRET PGY4 SEPTEMBER 17, 2014 MUSCULOSKELETAL COMPLICATIONS IN DIABETES.

Documents

Transcript of CATHERINE BARRET PGY4 SEPTEMBER 17, 2014 MUSCULOSKELETAL COMPLICATIONS IN DIABETES.