Disclosures Dr. Schafer: grant support, Bariatric Advantage and - - PDF document

4/13/2018 1

Challenging Cases in Metabolic Bone Disease and Mineral Metabolism

UCSF Diabetes Update and Advances in Endocrinology and Metabolism April 13, 2018

Dolores Shoback, MD

Professor of Medicine, UCSF Staff Physician, San Francisco VA Health Care System

Anne Schafer, MD

Associate Professor of Medicine, UCSF Staff Physician, San Francisco VA Health Care System

Disclosures

• Dr. Schafer: grant support, Bariatric Advantage and

Tate & Lyle

• Dr. Shoback: consultant, Radius Health, Inc.

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Case 1

70 year old woman referred by Orthopedic Surgery for management of osteoporosis

Medical History:

• Sciatica
• 2 lumbar spinal fusions for spinal stenosis (2009, 2015)
• Menopause age 51 (~1998), used hormone therapy x 5 years

Family History: + hip fracture in her mother and grandmother

• Osteoporosis diagnosed by DXA (2005): L-spine T-score -2.5
• Following the NOF Guidelines . . .
• Consider pharmacologic therapy for T-score ≤ -2.5, or higher T-scores if

risk factors present (+FH); she had no clinical fractures

• Endocrinologist started weekly alendronate 70 mg (highly compliant)

Case 1 - cont’d

70 year old woman referred by Orthopedic Surgery for management of osteoporosis

• 8 years into treatment with alendronate (2013) she slipped in

kitchen and fractured both wrists, requiring open reductions and internal fixations in separate surgeries

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Audience Question

70 year old woman with osteoporosis who is 8 years into therapy with alendronate and has sustained bilateral wrist fractures after a ground-level fall (2013) What would be your next step in management?

• A. Continue alendronate, as this event does not qualify as

treatment failure

• B. Switch to zoledronic acid or denosumab
• C. Switch to an anabolic agent (teriparatide or abaloparatide)
• D. Initiate a drug holiday

Case 1- Further Management

• Continue alendronate 70 mg weekly for 2 more years (2013-

2015) DXA (2015) – 10 yrs ALN completed:

• Lumbar spine (L1/L2): 0.969 g/cm2 (T-score: -1.6)
• Left femoral neck:

0.736 g/cm2 (T-score: -2.2)

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Whitaker et al, NEJM 2012

• Combined ALL morphometric and clinical vertebral and ALL

nonvertebral fractures (% of pts)

• Numbers – not large (all post-hoc)
• FLEX/Alendronate – 1099 pts
• Risedronate – 164 pts
• Zoledronic acid – 1233 pts

** BENEFIT – clear in first 3-5 years - NOT AFTER

** ** ** **

FDA Analysis 2012 FLEX Study Showed Reduction in Vertebral Fractures with 10 vs 5 years Alendronate: Clinical Subgroup Analyses

Black, Cummings et al, NEJM, 2012

GROUP RISK DIFF NNT* All women in study 2.9% 34 FN T < - 2.5 4.8% 21 FN T - 2.0 to - 2.5 3.0% 33 NO prevalent VFx and FN T < - 2.5 4.2% 24 Prevalent VFx FN T < - 2.5 5.8% 17 FN T - 2.0 to - 2.5 5.8% 17

* for 5 more years

Her vertebral fracture status at the time was unknown

Underline = best NNTs

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Case 1- Further Management

DXA (2015):

• Lumbar spine (L1/L2):

0.969 g/cm2 (T-score: -1.6)

• Left femoral neck:

0.736 g/cm2 (T-score: -2.2)

• Now, after 10 years treatment with alendronate, with increasing number of

atypical fractures reported in the literature, the patient herself asked to stop alendronate

Task Force Report on Managing Osteoporosis Patients After Long-Term Bisphosphonate Treatment.

(Adler R, et JBMR, 2016)

4/13/2018 6

Case 1- Further Management

DXA (2015):

• Lumbar spine (L1/L2):

0.969 g/cm2 (T-score: -1.6)

• Left femoral neck:

0.736 g/cm2 (T-score: -2.2)

• Now, after 10 years treatment with alendronate, with increasing number of

atypical fractures reported in the literature, the patient herself asked to stop alendronate

• Her physician switched her to denosumab

After 2 years - DXA (2017):

• Lumbar spine (L1/L2): 1.007 g/cm2 (T-score: -1.3) (+ 4%)
• Left femoral neck: 0.758 g/cm2 (T-score: -2.0) (+ 3%)

Case 1 – More History

• In 2017 - she retired from work, increased her exercise

(vigorous daily walking)

• 3 months prior to evaluation in our clinic: noted right leg

pain, attributed to ‘sciatica’ (in radicular distribution), making ambulation difficult (started to use cane to walk), pain slowly intensified

• 2 months prior: after a vigorous “power walk”, she

developed more intense right leg pain the next day, and she went to see her internist

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Xray of Pelvis and Right Femur

• Negative for

fracture

• No clear

etiology for her pain

Case 1 - Additional History

• While walking around at home

the very next morning, right leg pain intensified, and she could not get up from the bathroom

• Taken to emergency room by

family

• Xray right hip/femur showed an

acute subtrochanteric fracture

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Atypical Femur Fractures

• Subtrochanteric or femoral diaphyseal fractures in pts on

BP’s or denosumab

• “Stress” or insufficiency fractures
• 3-50 cases/100,000 person-yrs; long-term use 

~100/100,000 person-yrs

• Duration of BP treatment: > 3 years, median ~7 years
• Lower limb geometry, Asian ethnicity may contribute
• Most studies found association with glucocorticoid use

Shane E et al, JBMR, 2010 and 2014 Shane E et al, JBMR, 2014

At least 4/5:

4/13/2018 9

Case 1 - Management

• Open reduction and internal fixation,

with intramedullary rod/nail

• Discharged home with ongoing

physical therapy

• Slow recovery, continued pain with

weight bearing and unable to participate in physical therapy

• Thought to have delayed healing by

Xray (per orthopedist)

• Referred to clinic to discuss medical

management of non-healing fracture, now 8 weeks after initial trauma

In Clinic Evaluation

• Physical Exam: petite woman, height 5’5” (165.1

cm), weight 120 lbs (54.4 kg), normal vital signs; pain with internal and external rotation of right hip, using a wheelchair

• Labs: normal chemistries, Ca, PTH, phosphate, 25-

OH vitamin D, TSH, free T4, tissue transglutaminase Ab, complete blood count - all normal

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Current Management Strategies: Atypical Femur Fractures

• Pain in thigh or groin in pt on BP or denosumab  should be

investigated

• Modalities: X-ray, MRI, CT; assess both sides
• Extended DXA of femur
• If you diagnose an AFF, BP or D-Mab should be stopped
• Surgery (femoral rod) - recommended for complete fractures and

for painful incomplete fractures

• Minimal pain and incomplete fracture  can try non-weight bearing x 2-3

months, then surgery if not healed

• Delayed healing – not uncommon
• Anabolic therapy? Several reports of enhanced healing, but others

with no effects on healing (teriparatide)

• No RCT’s

Bone Biopsies Before and After 12 Months Treatment with TPTD in 15 Patients with AFF’s

• Average 7 years of ALN
• Bone histomorphometry –

bone formation rates

• AT BASELINE: 7/15 pts

had unmeasurable parameters (e.g., BFR/BV) and 8/15 had measurable parameters but below control population

• Responses to 12 months
• f teriparatide

Miller PD, McCarthy EF, Sem Arth Rheum, 2014

4/13/2018 11

Case 1 – Further Evaluation

CT Scan – right and left femur (9-10 weeks post-trauma):

• healing abundant bridging callus formation noted at proximal

right femoral diaphysis

• nail in satisfactory alignment
• NO CT evidence for “stress reactive changes” or cortical

thickening involving left femur

• Was now able to participate in physical therapy, and

deferred pharmacologic intervention

• Being followed with plan to monitor BMD and clinical status

Case 2

74 year old man referred for evaluation of history of fractures

Present Illness:

• + h/o multiple fractures beginning in childhood (very active,

lived on ranch, did heavy labor)

• Fractures stopped as an adolescent
• Deployed to Viet Nam where he sustained a painful vertebral

compression fracture in combat exercise, took a desk job until the war ended

• Sustained L femur fracture in 2000 with mild fall, rod placed

Orthopedic surgeon told him  “. . . you may have

• steogenesis imperfecta”

4/13/2018 12

Case 2 – cont’d

74 year old man referred for evaluation of history of fractures

Review of systems:

• + bilateral hearing loss; + poor dentition; no joint laxity, chest pain

Past medical history:

• L2 superior endplate fracture noted on 6/2001 xray
• New T12 compression fracture detected on surveillance CT for

following thoracic aortic aneurysm in 2017

• Aortic aneurysm: no change in size since 2014

Case 2 – cont’d

Social history:

• Smoked cigars (1968-73) in Army
• Quit heavy drinking ~age 34; beer drinker until ~age 64
• Works as ranch hand, does horseshoeing, no riding horses

Medications:

• amlodipine 10 mg
• lisinopril 5 mg bid
• metoprolol succinate 25 mg
• vit D3 1,000 IU qd

4/13/2018 13

Case 2 – cont’d

Family history:

• No aneurysms, joint laxity, or sudden cardiac death
• Mother died of cancer (age 57), father – old age (age 93)
• 1 brother – alcoholism, had fractures but traumatic

Age 74 proband Age 50, multiple frxs Age 25 Age 14 broken hip at age 1,

• ther med problems

Age 13

Case 2 – Physical Exam

• Ht: 67 in [170.2 cm]; weight: 201.4 lbs, nl VS
• NAD, well developed and well appearing
• HEENT: +blue sclerae; lower teeth dysplastic, small and

translucent.

• CV: no murmurs
• Lungs: clear, barrel chested
• Bones/Joints: +kyphosis, no joint laxity or deformity
• Skin: sun damage to forearms bilaterally, no skin laxity
• Neuro: intact, slight limp

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Spine Xrays - 2018

• Chronic T12 cx frx

(unchanged)

• Chronic L2 cx frx

(unchanged)

• OSTEOPENIA
• Multilevel

degenerative changes &

• steophytes
• Aortic vascular

calcifications

DXA – January, 2018

(first he ever had)

Lumbar spine BMD (g/cm2) T score L1 0.605

• 4.3

L2 0.756

• 3.1

L3 0.850

• 2.3

L4 0.930

• 1.5

Total 0.795

• 2.7

Hip BMD (g/cm2) T score Femoral neck 0.632

• 2.2

Total hip 0.767

• 1.8

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• SPINE:
• L1: 33.6
• L2: 32.5
• L3: 31.6
• Average BMD: 32.6 mg/cc
• T score -5.19

CT Densitometry – January, 2018

Case 2 – Labs

• Chem panel, creatinine: normal; eGFR 71 mL/min
• TSH 0.45 uU/mL (0.35 - 5.00); Ca 9.6 mg/dL (nl); phos 3.0

mg/dL (nl); albumin 4.6 G/dL (nl); alk phosphatase 102 (40-125)

• 25-(OH) vitamin D 37.8 ng/mL (20–50); testosterone 238.0

ng/dL (175-781); PTH 25.7 pg/mL (15-88)

• Serum P1NP 34 mcg/L (30-110); serum CTX 116 pg/mL (87-

345)

• 24 hour urine: Ca 150 mg, creatinine 1535 mg

Endocrine/metabolic 2 o causes for osteoporosis ruled out

4/13/2018 16

Audience Question

How would you manage this 74 y.o. ranch worker with 2 vertebral fractures, very low T-scores, and normal labs?

• A. No pharmacologic therapy, as patient is clinically stable
• B. Start bisphosphonate
• C. Start anabolic therapy
• D. Obtain genetics consult

Osteogenesis Imperfecta

• Quantitative or qualitative defect in type 1 collagen synthesis
• 85% of cases: autosomal dominant mutations in COL1A1 and

COL1A2

• 15% of cases: dominant or recessive mutations in non-

collagenous proteins involved in collagen processing or

• steoblast differentiation/function
• Rare  ~11/100,000 population
• Phenotype: bone (fragility, fractures, pain, deformity, scoliosis);

cardiovascular system (valvular disease, aortic aneurysm); lungs; muscle weakness; ligamentous laxity; hearing loss; dentinogenesis imperfecta

4/13/2018 17

Osteogenesis - Features

A – blue sclerae B – dentinogenesis imperfecta C – limb deformities D – pectus carinatum E - clinodactyly F - scoliosis

Marini JC et al, Nat Rev Dis Primers, 2017

Classic Clinical Phenotype – Types I-IV . . . and more

• Type I – blue sclerae, near normal stature, late
• nset hearing loss (teeth okay)
• Type II – perinatal lethal form
• Type III – progressive deforming variety
• Type IV – white sclerae, short stature, bone

deformity, dentinogenesis, more severe than type I, less severe than II and III

• Types V through XVII

Marini JC et al, Nat Rev Dis Primers, 2017

This patient

4/13/2018 18

Treatment Options (Orwoll E et al, J Clin Inv, 2014)

• Children – treated with bisphosphonates  reduced

bone turnover, higher BMD, and reduced fractures, pain

• Adults – small studies with oral or IV bisphosphonates

 increased BMD in some with OI, not powered for fracture

• RCT of 79 adults with OI, treated with teriparatide (20

mcg) vs placebo x 18 months

• 51 pts (type 1), 14 pts (type III), 12 pts (type IV)

DXA BMD Changes with Teriparatide vs Placebo

Orwoll E et al, J Clin Inv, 2014

4/13/2018 19

Post-hoc evaluation

• f OI

subgroups:

Type I OI had significant treatment effects, but Type III/IV had no response at any ROI or time point

Orwoll E et al, J Clin Inv, 2014

Type I Type III/IV

Case 2 – Conclusion

Genetic testing and family screening  Likely teriparatide

4/13/2018 20

Case 3

64 year old man seen as an inpatient for new-onset hypercalcemia.

• One month prior to the hospitalization: presented to his PCP

with a 3-month history of low energy, dyspnea on exertion, and a 30-pound weight loss

• No fevers or chills, no cough
• + Polydipsia and polyuria
• + Abdominal distention and constipation

Case 3 – cont’d

64 year old man seen as an inpatient for new-onset hypercalcemia.

• Past medical history:

▪ COPD on home O2 ▪ SCC of the lung, dx in 2015, s/p LUL lobectomy ▪ Surveillance CT negative in 2016

• Medications: albuterol, budesonide, tiotropium, amlodipine, atorvastatin

▪ No calcium or vitamin D supplements, no antacids

• Family history: father d. brain tumor, mother d. MVA
• Social history: Navy, 30 pack-year smoking, 1-2 beers/day

4/13/2018 21

Case 3 – Physical Exam

• Vital signs: T 98, BP 111/70, HR 102, RR 18, 95% on 2L/min,

weight 144 lbs (174 prior), BMI 21 kg/m2

• Chronically ill-appearing
• Diminished air movement bilaterally, but breathing comfortably
• Hypoactive bowel sounds, mild diffuse ttp, no rebound or

guarding

• No bone tenderness

Case 3 – Initial Outpatient Labs

▪Calcium 12.3 mg/dL (was 8.7 mg/dL one year prior)

▪ Corrected Ca 13.5 mg/dL

▪Albumin 2.5 g/dL, phos 2.1 mg/dL ▪Total protein 7.7 g/dL ▪Total bili 0.5, AST 9, ALT 8, alk phos 198 (nl to 125) ▪TSH 0.57 uU/mL ▪CXR - no lung masses

3.7 29 0.6 133 98 5 9 464 12 151

4/13/2018 22

Case 3 – cont’d

• PCP referred patient to ED for IVF and additional evaluation

and treatment

• Pt refused
• Repeat calcium 11.8 mg/dL corrected 12.8 mg/dL
• PTH 1.8 pg/mL (nl 15-88)
• PCP again referred pt to infusion clinic: 2 L IV saline, 4 mg

zoledronic acid

• Two days later: corrected calcium improved to 10.4 mg/dL

PTH high (or inappropriately normal)

Primary hyperparathyroidism Familial hypocalciuric hypercalcemia (types 1, 2, 3) Drugs: lithium, thiazides

PTH low

Malignancy 1,25(OH)2D excess Vitamin D or A toxicity Milk-alkali syndrome Immobilization Hyperthyroidism, adrenal insufficiency

Approach to Hypercalcemia

Measure Intact PTH (concern)

4/13/2018 23

Hypercalcemia of Malignancy

• 90% of hyperCa in hospitalized pts
• Etiology
• Osteolytic bone metastases (~20%)
• Breast cancer, multiple myeloma
• PTHrP production (~80%)
• Solid tumors of head/neck, lung, renal, breast, bladder, ovary
• Ectopic 1,25(OH)2D
• Lymphomas
• Usually late in the course of a malignancy, when tumor

burden is large

Audience Question

What is the etiology of his hypercalcemia?

• A. Osteolytic metastases
• B. PTHrP production
• C. 1,25(OH)2D production
• D. None of the above

4/13/2018 24

Humoral Hypercalcemia of Malignancy

• PTH-related protein (PTHrP):

normally expressed in small amounts by a variety of tissues

• Binds to PTH-1 receptor, activating

similar post-receptor pathways

• But less likely than PTH to stimulate

1,25(OH)2D production

• Primary mechanism: increased intestinal

calcium absorption

• 1,25(OH)2D-mediated bone resorption

may also play role

• Generally responds to glucocorticoids

Ectopic 1,25(OH)2D Production

4/13/2018 25

Case 3 – cont’d

• Serum calcium increased quickly after the zoledronic acid:

10.4  12.9 mg/dL (corrected)

• PCP ordered second dose of zoledronic acid, 2 wks after

the first

• Patient felt worse and presented to ED  admitted

Case 3 – Additional Lab Data

Date Ca

(uncorr)

alb phos Cr PTH (15-88) 25OHD

1,25OH2D (18-72)

PTHrP (14-27)

1/12/18

12.3 2.5 2.1 0.54 1.8

1/13/18

11.8 2.8 2.4 0.49

IVF + ZOL 4 mg IV

1/15/18

9.1 2.4 1.4 0.45

1/19/18

9.9 3.0 2.6 0.61

1/29/18

12.1 0.56

IVF + ZOL 4 mg IV

2/2/18

11.2 3.0 1.8 0.55

2/3/18

10.4 2.6 1.5 0.49

2/6/18

10.9 2.5 2.3 0.46

4/13/2018 26

Case 3 – Additional Lab Data

Date Ca

(uncorr)

alb phos Cr PTH (15-88) 25OHD

1,25OH2D (18-72)

PTHrP (14-27)

1/12/18

12.3 2.5 2.1 0.54 1.8 41.8

1/13/18

11.8 2.8 2.4 0.49 103

IVF + ZOL 4 mg IV

1/15/18

9.1 2.4 1.4 0.45

1/19/18

9.9 3.0 2.6 0.61 30

1/29/18

12.1 0.56

IVF + ZOL 4 mg IV

2/2/18

11.2 3.0 1.8 0.55

2/3/18

10.4 2.6 1.5 0.49

2/6/18

10.9 2.5 2.3 0.46 88 52

Case 3 – Additional Lab Data

Date Ca

(uncorr)

alb phos Cr PTH (15-88) 25OHD

1,25OH2D (18-72)

PTHrP (14-27)

1/12/18

12.3 2.5 2.1 0.54 1.8 41.8

1/13/18

11.8 2.8 2.4 0.49 103

IVF + ZOL 4 mg IV

1/15/18

9.1 2.4 1.4 0.45

1/19/18

9.9 3.0 2.6 0.61 30

1/29/18

12.1 0.56

IVF + ZOL 4 mg IV

2/2/18

11.2 3.0 1.8 0.55

2/3/18

10.4 2.6 1.5 0.49

2/6/18

10.9 2.5 2.3 0.46 88 52

4/13/2018 27

Imaging Studies

• CT abdomen/pelvis:
• Multiple hypodense liver masses, largest 7.9 cm, new

compared to prior.

• No bony lesions.
• MRI brain:
• Possible left occipital bone skull base metastasis.

PET/CT

4/13/2018 28

Pathology

FNA of liver lesion performed  Metastatic squamous cell carcinoma

Treatment of Hypercalcemia

• Treat the underlying cause
• Hydration
• +/- Loop diuretic after volume replete
• +/- Calcitonin for (weak) early effect
• Antiresorptive to block Ca mobilization from bone
• Glucocorticoids to block intestinal absorption
• (Dialysis against low Ca dialysate)

4/13/2018 29

What explains this patient’s hypercalcemia?

• Chronically elevated PTHrP
• Chronically elevated 1,25(OH)2D
• Presumed chronic stimulation of renal 1-hydroxylase

 Our patient needs dual inhibition of bone resorption and intestinal calcium absorption

Denosumab for Hypercalcemia

• Not cleared by kidney
• Option for bisphosphonate-

refractory hypercalcemia

• 33 pts with corrected Ca

> 12.5 mg/dL after BP  DMAB 120 mg SQ weekly x 4 weeks then monthly

• 21/33 (64%) had Ca

< 11.5 mg/dL at 10 days

• No head-to-head trials

Hu et al, JCEM, 2014

4/13/2018 30

Case 3 – cont’d

 Denosumab 120 mg SQ  Prednisone 40mg daily  Currently deciding between cancer-directed therapy vs. comfort-based care

Questions?

4/13/2018 31

Extra Slides

Bone Formation Marker Changes with Teriparatide vs Placebo

Orwoll E et al, J Clin Inv, 2014

4/13/2018 32

Genetic Classification I

Gene Protein Type Inheritance Phenotype Collagen synthesis and structure defects

COL1A1, COL1A2 COL1A1, COL1A2 I, II, III, IV AD “Classic”

Compromised bone mineralization

IFITM5 SERPINF1 Bone-restricted interferon-induced transmembrane protein- like protein Pigment epithelium derived factor V VI AD AR Normal to severe bone loss, +/- blue sclerae, +/- hearing loss Mod to severe bone deformity

Abnormal collagen post-translational modification CRTAP, P3H1, PPIB

Cartilage-assoc protein,

• ther collagen processing

enzymes

VII, VIII, IX AR Severe bone abnormalities (rhizomelia)

(Marini JC et al, Nat Rev Dis Primers, 2017)

Genetic Classification II

Gene Protein Type Inheritance Phenotype Compromised collagen processing and crosslinking

SERPINH1, FKBP10, PLOD2, BMP1 HSP47, FK506 binding protein, Lysyl hydroxylase 2, Bone morphogenic protein 1 X, XI, no number, XII AR Mod-severe bone deformities, blue-grey- normal sclerae, +/- teeth, joint contractures

Altered osteoblast differentiation and function

SP7 TMEM38B WNT1 CREB3L1 SPARC MBTPS2 Osterix Cation channel type B Wnt 1 proto-oncogene Signaling protein Osteonectin Membrane bound transcription factor site 2 protease XII XIV XV XVI XVII XVII AR (mostly) Mostly severe bone fragility and deformity, delayed teeth in some, neuro problems in some, scoliosis in some, +/- blue sclerae (Marini JC et al, Nat Rev Dis Primers, 2017)