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
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
Slide 6
DIABETIC CHEIROARTHROPATHY PATHOPHYSIOLOGY: glycosylation of
collagen in skin and periarticular tissues collagen degradation
Diabetic microangiopathy Diabetic neuropathy Clin Rheumatol (2013)
32:527533
Slide 7
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
Slide 8
DIABETIC CHEIROARTHROPATHY TREATMENT: Physiotherapy to increase
range of motion and improve strength Optimize glycemic control
Encourage smoking cessation Clin Rheumatol (2013) 32:527533
Slide 9
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
Slide 10
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
Slide 11
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
Slide 12
FLEXOR TENOSYNOVITIS TREATMENT Activity modification NSAID
Splinting Corticosteroid injection into the tendon sheath Surgical
release Clin Rheumatol (2013) 32:527533
Slide 13
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
Slide 14
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
Slide 15
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
Slide 16
Clin Rheumatol (2013) 32:527533, www.uptodate.com
Slide 17
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
Slide 18
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
Slide 19
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
Slide 20
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
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)
Slide 23
MUSCULOSKELETAL COMPLICATIONS AND THE DDCT/EDIC TRIAL
Slide 24
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
Slide 25
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
Slide 26
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
Slide 27
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
Slide 28
Diabetes Care 2014;37:1863-1869
Slide 29
Association of prevalence of cheiroarthropathy by tertiles of
time-weighted HgA1C during the DCCT/EDIC (1983-2011)
Slide 30
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
Slide 31
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%)
Slide 32
OTHER MSK COMPLICATIONS
Slide 33
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
Slide 34
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
Slide 35
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
Slide 36
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
Slide 37
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
Slide 38
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%
Slide 39
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
Slide 40
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
Slide 41
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
Slide 42
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
Slide 43
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
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
Slide 46
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
Slide 47
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
Slide 48
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
Slide 49
NEUROPATHIC OSTEOARTHROPATHY
Slide 50
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
Slide 51
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
Slide 52
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
Slide 53
J of foot and ankle surgery (2013) 740-749
Slide 54
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
Slide 55
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
Slide 56
Slide 57
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
Slide 58
OSTEOPOROSIS
Slide 59
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,
Slide 60
Risk factors for osteoporotic fractures in DM Jackuliak et al.
2014
Slide 61
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
Slide 62
OSTEOPOROSIS Bone mineral density is increased in TIIDM
trabecular bone with cortical bone BMI plays a role in BMD
determination
Slide 63
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
Slide 64
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
Slide 65
Hamman et al: Nature Reviews Endocrinology 2012;8:297-305
Slide 66
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
Slide 67
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
Slide 68
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
Slide 69
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
Slide 70
Maturitas 2013(76):253-9
Slide 71
Jackuliak et al. 2014
Slide 72
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.
Slide 73
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
Slide 74
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
Slide 75
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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
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