CKD- MBD / Osteoporosis in the elderley

the management dilemma

Dr Ayman Seddik , Msc , MD

Assistant Professor of Nephrology Ain Shams University

Consultant nephrologist

OUTLINE

• CKD MBD & OSTEOPOROSIS aetiology prevelance and impact on mortality and morbidity in elderley population

• Management based on stage of chronic kidney disease

Table 1 Differences between CKD–MBD and postmenopausal osteoporosis

Ott, S. M. (2013) Therapy for patients with CKD and low bone mineral density Nat. Rev. Nephrol. doi:10.1038/nrneph.2013.182

Osteoporosis

Osteoporosis is defined as a skeletal disorder characterized by compromised

bone strength predisposing to an increased risk of fracture.

NIH Consensus Development Conference, March 2000

Normal Bone Osteoporotic Bone

Vertebral Fracture Cascade

THE HUMAN COST

Downward Spiral

Denosumab: Overview

• Fully human monoclonal antibody-IgG2 isotype

• High affinity and specificity for human RANK Ligand

• Pharmacokinetics (SC): similar to other fully human IgG2 monoclonal antibodies

– Absorption is rapid and prolonged (Cmax ≈1-4 wks postdose)

– Long half-life ≈34 days with max dose

– Distribution ≈ intravascular volume

– Clearance ≈ reticuloendothelial system

– No kidney filtration or excretion of intact molecule

Bekker PJ et al. J Bone Miner Res. 2004;19:1059-1066. Boyle WJ et al. Nature. 2003;423:337-342.

Mechanism of Action for Denosumab

Growth Factors Hormones Cytokines

Bone

CFU-M = colony forming unit macrophage

Osteoblast Lineage

Osteoclast

CFU-M

Pre-Fusion Osteoclast

Multinucleated Osteoclast

RANK

RANKL

OPG

denosumab

KDIGO Clinical Practice Guideline

Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease - Mineral and Bone Disorder (CKD-MBD)

Guideline Outline

Chapter 4.1: Treatment of CKD-MBD Targeted at Lowering High Serum Phosphorus and Maintaining Serum Calcium

Chapter 4.2: Treatment of Abnormal PTH Levels in CKD-MBD

Chapter 4.3: Treatment of Bone with Bisphosphonates, other Osteoporosis Medications, and Growth Hormone

Chapter 5: Evaluation and Treatment of Kidney Transplant Bone Disease

Chapter 6: Summary and Research

Definition of

CKD-Mineral and Bone Disorder

A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:

Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism

Abnormalities in bone turnover, mineralization, volume, linear growth, or strength Vascular or other soft tissue calcification

Moe S, et al. Kidney Int 69: 1945, 2006

Classification of Renal Osteodystrophy

Turnover High Normal Low

Mineralization Normal Abnormal

Volume High Normal Low

Slide courtesy of Susan Ott Kindly provided by Dr. Susan M. Ott

Moe, SM et al. ACKD: 3-12, 2007

Prevalance of types of bone disease as determined

by bone biopsy in patients with CKD-MBD

AD, adynamic bone; OF, osteitis fibrosa; OM, osteomalacia.

Treatment of CKD-MBD:

Phosphorus and Calcium 4.1.1. In patients with CKD stages 3–5, we suggest

maintaining serum phosphorus in the normal

range (2C). In patients with CKD stage 5D, we

suggest lowering elevated phosphorus levels

toward the normal range (2C).

4.1.2. In patients with CKD stages 3–5D, we

suggest maintaining serum calcium in the normal

range (2D).

Treatment of CKD-MBD:

Phosphorus and Calcium 4.1.3. In patients with CKD stage 5D, we suggest

using a dialysate calcium concentration between

1.25 and 1.50 mmol/l (2.5 and 3.0 mEq/l) (2D).

4.1.4. In patients with CKD stages 3–5 (2D) and 5D

(2B), we suggest using phosphate-binding agents

in the treatment of hyperphosphatemia. It is

reasonable that the choice of phosphate binder

takes into account CKD stage, presence of other

components of CKD–MBD, concomitant therapies,

and side-effect profile (not graded).

Treatment of CKD-MBD:

Phosphorus and Calcium 4.1.5. In patients with CKD stages 3–5D and hyperphosphatemia, we recommend restricting the dose of calcium-based phosphate binders and/or the dose of calcitriol or vitamin D analog in the presence of persistent or recurrent hypercalcemia (1B).

In patients with CKD stages 3–5D and hyperphosphatemia, we suggest restricting the dose of calcium based phosphate binders in the presence of arterial calcification (2C) and/or adynamic bone disease (2C) and/or if serum PTH levels are persistently low (2C).

Osteoporosis

Osteoporosis is defined as a skeletal disorder characterized by compromised

bone strength predisposing to an increased risk of fracture.

NIH Consensus Development Conference, March 2000

Normal Bone Osteoporotic Bone

THE HUMAN COST

Downward Spiral

Osteoporosis Prevention and

Treatment

Age

Hormonal Replacement

Bisphosphonates Strontium

SERM

20 40 60 80

Vitamin D

PTH

Life Style

Treatment choice

Vertebral Fracture Cascade

Osteoporosis in Men Has Its Time Come?

Hip Fracture:

Devastating Event Mortality rate same as breast cancer 20% excess mortality in the first year 50% incapacitation 20% of females need assisted living or nursing home 80% of 75 yo preferred death to hip fx & nsg hm Cooper C, et al. Am J Epidemiol. 1993;137:1001

The Osteoporotic Event: Hip Fracture

#1: Questions about Osteoporosis

When should Bone Density Measurement

be performed?

Diagnostic criteria* Classification

T is above or equal to -1 Normal

T is between -1 and -2.5 Osteopenia (low

bone mass)

T is -2.5 or lower Osteoporosis

T is -2.5 or lower + fx = Severe or est.

osteoporosis

*Measured in "T scores." T score indicates the number of standard deviations below or above the average peak bone mass in young adults.

WHO Criteria for Diagnosis of Bone Status

World Health Organization

Diagnostic Criteria

DIAGNOSIS BMD CRITERIA*

Normal within 1 SD of a “young normal” adult (T-score at -1.0 and above) Osteopenia between 1 and 2.5 SD below that of a “young normal” adult (T-score between -1 and -2.5) Osteoporosis 2.5 SD or more below that of a “young normal” adult (T-score at or below -2.5) Severe Osteoporosis 2.5 SD or more below that of a “young normal” adult and fracture(s)

T-score is the number of SDs above or below the average BMD value for young, normal adults of the same sex BMD = Bone mineral density SD = Standard deviation *Measured at the hip, spine, or wrist

60

70

80

90

100

30 40 50 60 70 80 90

Age

Rel

ativ

e B

MD

(%)

Forearm

Spine

Hip and Heel

0

1000

2000

3000

4000

35- 39

85+

Colles'

Vertebrae

Hip

Age

An

nu

al F

ract

ure

In

cid

ence

Cooper C. Baillières Clin Rheumatol. 1993;7:459–477. Faulkner KG. J Clin Densitom. 1998;1:279–285.

As BMD Decreases Fracture Risk

Increases * Remember: Only ~1/3 of spine fractures are acutely painful

Bone Mass Measurement Act

Federal Register 1997 for HCFA/CMS

Medicare Osteoporosis Measurement Act 2003

1. Women with estrogen deficiency

2. Spine x-ray evidence of fracture or OP

3. Glucocorticoid therapy (3mos, 5 mg/d)

4. Primary Hyper-PTH

5. Follow-up treatment (23 months unless medical reason for sooner e.g. steroids)

USPSTF 2010 Recommendations :

Screening for Osteoporosis BMD testing for women 65 & older

BMD in 60-64 yo if ↑ fx risk

Use WHO FRAX® risk tool If clinical based fracture risk of 9.3% then order bone density measurement

Nelson et al Ann Int Med July 2010

WHO Fracture Risk Prediction

10-year Risk Assessment for Women

(CAROC Basal Risk)

Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

10-year Risk Assessment for Women

(CAROC Basal Risk)

Age Low Risk Moderate Risk High Risk

50 above -2.5 -2.5 to -3.8 below -3.8

55 above -2.5 -2.5 to -3.8 below -3.8

60 above -2.3 -2.3 to -3.7 below -3.7

65 above -1.9 -1.9 to -3.5 below -3.5

70 above -1.7 -1.7 to -3.2 below -3.2

75 above -1.2 -1.2 to -2.9 below -2.9

80 above -0.5 -0.5 to -2.6 below -2.6

85 above +0.1 +0.1 to -2.2 below -2.2

Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

Risk Assessment with CAROC:

Important Additional Risk Factors

Factors that increase CAROC

basal risk by one category

(i.e., from low to moderate or

moderate to high) Fragility fracture after age 40*1,2

Recent prolonged systemic

glucocorticoid use**2

1. Siminoski K, et al. Can Assoc Radiol J 2005; 56(3):178-188. 2. Kanis JA, et al. J Bone Miner Res 2004; 19(6):893-899. Return to case

* Hip fracture, vertebral fracture, or multiple fracture events should be considered high risk ** >3 months use in the prior year at a prednisone-equivalent dose ≥ 7.5 mg daily

Example of Applying the FRAX Tool

Which Woman is at Higher Fracture Risk?

54 year old smoker with a T-score of -2.0 or

81 year old with no prior fracture with a T-score of -1.4

10 year risk of hip fracture = 2.5%; major osteoporotic fracture = 10%

10 year risk of hip fracture = 3.2%; major osteoporotic fracture = 26%

2012 FRAX update

(& shortcomings) 1. Current version is 3.7

2. Reduced hip fracture rates due to trends

3. Deliberate exclusion of risk factors &”dose”:

Vitamin D deficiency, falls, dementia, bone turnover, other drugs

Number & severity of fractures, dose of ETOH/Tobacco

4. Low spine BMD not included but can compensate for it: Leslie WD,

Osteoporos Int (2011) 22:839–847

5. “Untreated” defined: In past year : no ET/HT, SERM , calcitonin, PTH ,denosumab

No bisphosphonate for the past two years ( or oral for <2 months)

Calcium & Vit D are not “treatment”

Ettinger et al Osteoporosis Int.2010 (21)25-33 www.shef.ac.uk/FRAX; www.iscd.org/visitors/resources/fractureriskmodels.cfm

#2: Questions about Osteoporosis

Are calcium & Vitamin D supplements needed?

1 – YES

2 -- NO

Calcium: What Is the Right Dose?

A longitudinal and prospective cohort study,(Swedish Mammography Cohort)

61 433 women (born between 1914 and 1948) were followed up for 19 years.

5022 of these women participated in the subcohort.

Conclusions:

Dietary calcium < 700 mg/ day = increased risk of hip fracture, any fracture,

and of osteoporosis

The highest reported calcium intake did not further reduce the risk of

fractures of any type, or of osteoporosis, but was associated with a higher

rate of hip fracture Warensjö E et al. BMJ 2011;342:bmj.d1473

EPIC-Heidelberg cohort 25,540 local residents aged 35-64 years Excluded diagnosis of MI, stroke, or transient ischemic attack at baseline (n = 1322) Self-administered food questionnaire Interview to assess ever use of vitamins and calcium supplements Incident cardiovascular events during follow-up were reported by participants or their next of kin in follow-up surveys. Reported cardiovascular events were verified by tracking medical records or official death certificates.

Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study

Heart 2012;98:920-925.

Calcium Intake and CV disease

In conclusion, this study suggests that increasing dietary calcium intake from diet might not confer significant cardiovascular benefits, while calcium supplements, which might raise MI risk, should be taken with caution.

www.nof.org

Recommended Calcium Intake

From diet and supplements combined: 1200 mg daily Several different types of calcium

supplements are available

Evidence shows a benefit of calcium on reduction of fracture

risk1

Concerns about serious adverse effects with high-dose supplementation2-4

1. Tang BM, et al. Lancet 2007; 370(9588):657-666. 2. Bolland MJ, et al. J Clin Endocrinol Metab 2010; 95(3):1174-1181.

3. Bolland MJ, et al. BMJ 2008; 336(7638):262-266. 4 Reid IR, et al. Osteoporos Int 2008; 19(8):1119-1123.

What about Vitamin D?

Liu et all Heart Failure Society of America San Diego Sept 2010 Binkley et al ,Endocrinol Metab Clin N Am 2010 Bischoff-Ferrari H. et al. JAMA. 2005;293(18):2257-2264 Janssen HCJP, et al. Am J Clin Nutr. 2002;75:611

Optimal level: bone health >32ng/ml IOM: for general pop =20ng/ml Deficiency: falls, 3.4 X CHF death

Possibly cancer, DM, autoimmune disease,etc., remember Vit E?

Supplements: assoc with decreased mortality 1000 IU daily increase level~ 10ng/ml Too much at once? 500,000 IU and falls Toxicity?

Recommended Vitamin D Supplementation

Group

Recommended

Vitamin D

Intake (D3)

Adults < 50 without osteoporosis or conditions

affecting vitamin D absorption

400 – 1000 IU daily

(10 mcg to 25 mcg

daily)

Adults > 50 or high risk for adverse outcomes from

vitamin D insufficiency (e.g., recurrent fractures or

osteoporosis and comorbid conditions that affect

vitamin D absorption)

800 – 2000 IU daily

(20 mcg to 50 mcg

daily)

Hanley DA, et al. CMAJ 2010; Jul 26. [epub before print].

2012 Questions about

Osteoporosis

Are Bisphosphonates safe?

3. ONJ

4. Treatment duration

5. Esophageal cancer

6. Atypical fractures

FDA Approved Osteoporosis Medications

Drug Post Menopausal OP Steroid OP Male OP

Prevention Treatment Prevention Treatment

Alendronate

Risedronate

Ibandronate

Zoledronate

Raloxifene

Estrogen

Calcitonin

Denosumab *

Teriparatide

First Line Therapies with Evidence for Fracture

Prevention in Postmenopausal Women*

Type of

Fracture

Antiresorptive therapy

Bone

formation

therapy

Bisphosphonates

Denosumab Raloxifene

Hormone

therapy

(Estrogen)**

Teriparatide Alendronate Risedronate

Zoledronic

acid

Vertebral

Hip - -

Non-

vertebral+ -

* For postmenopausal women, indicates first line therapies and Grade A recommendation. For men requiring treatment, alendronate, risedronate, and zoledronic acid can be used as first line therapies for prevention of fractures [Grade D]. + In clinical trials, non-vertebral fractures are a composite endpoint including hip, femur, pelvis, tibia, humerus, radius, and clavicle. ** Hormone therapy (estrogen) can be used as first line therapy in women with menopausal symptoms.

Bisphosphonates – Administration

Must be taken at least one-half hour before the first food, beverage, or medication of the day with plain water only (1 hour prior for monthly ibandronate) Should only be taken upon arising for the day Tablet should be swallowed with a full glass of water (8 oz) and patients should remain upright, walking, standing, or sitting for at least 30 minutes (60 minutes for monthly ibandronate) Should supplement with calcium/vitamin D if dietary intake inadequate

Bisphosphonates – Adverse Effects

Hypocalcemia (18%)

Hypophosphatemia (10%)

Musculoskeletal pain,

cramps – recent FDA

warning

• Gastrointestinal

– Abdominal pain

– Acid reflux

– Dypepsia

– Esophageal ulcer

– Gastritis

• Osteonecrosis of the jaw

(IV bisphosphonates)

• Visual disturbances (rare)

3. What is the Clinical

Presentation of ONJ? Signs &Symptoms:1

Asymptomatic or Facial pain, jaw pain Soft-tissue swelling,drainage Exposed,necrotic bone

Cultures: actinomyces2

Risk factors Cancer & concomitant therapies Poor oral hygiene Smoking Pre-existing dental disease, anemia, coagulopathy, and infection

Management Povidone-iodine & 0.12% chlorhexidine mouthwash Oral antibiotics and anti-inflammatory drugs Conservative debridement for necrotic tissue

Ruggiero SL, Hehrotra B, Rosenberg TJ, et al. J Oral

Maxillofac Surg. 2004;62:527-34.

1. Expert Panel Recommendations for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaws: June 2004

2. Naveau A. Joint Bone Spine 2005.

Melo MD, Obeid G. J Can Dent

Assoc 2005;71: 11-3.

Bisphosphonate-associated Osteonecrois(BON)

& American Dental Association

Oral bisphosphonate users:… very low risk for developing BON. Actual incidence unknown; estimates 0 to 1 in 2,260 Low risk for BON may be minimized but not eliminated. Oral health program: sound oral hygiene practices , regular dental care, … optimal approach to lower risk for BON. No validated diagnostic technique for BON risk. Discontinuing bisphosphonate therapy may not eliminate any risk for developing BON.

ADA Expert Panel Recommendations 2008

Femoral Shaft Fractures

In 2005, Odvina et al reported a series of nine patients with spontaneous, atypical fractures, all on

bisphosphonate therapy for a period of time ranging from 3 to 8 years. Four with fractures in the subtrochanteric region and one each with fractures of the sacrum, rib, ischium, pubic rami and lumbar spine.

6/9 had delayed or absent healing during management. Histology revealed over suppression of bone turnover, possibly linked to bisphosphonate usage, but other factors, i.e.. estrogens and glucocorticoid use left much room for debate.

Odvina et al JCEM2005;90:1294–1301

Figure 1

Atypical Fractures of the Femoral Diaphysis in Postmenopausal Women Taking Alendronate. Lenart, Brett; Lorich, Dean; Lane, Joseph New England Journal of Medicine. 358(12):1304-1306, March 20, 2008.

Figure 1 . Radiographs of Fractures of the Femoral Shaft Showing the "Simple with Thick Cortices" Pattern Panel A shows a fracture of the femoral shaft in an 83-year-old woman with a 9-year history of alendronate use. Panel B shows a similar fracture in a 77-year-old woman with a 5-year history of alendronate use.

Atypical Femoral Fracture

Shane et al, JBMR 25:2010;25:2267–2294.

Conventional AP radiograph of the pelvis (A) shows bilateral focal cortical thickening from

periosteal new bone formation (arrows). Corresponding bone scintigraphy (B)

demonstrates focal increased radionuclide uptake in the proximal lateral femoral cortices

(arrows). MRI images of the femurs (C) demonstrate subtle decreased signal on T1-

weighted and increased signal on T2-weighted images only of the right femur on

this section. Similar findings on AP DXA hip images (D) show focal bilateral cortical

thickening consistent with early, evolving femoral insufficiency fractures.

A B

D C

Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures in Older Women

L. Park-Wyllie, PharmD, MS, M. Mamdani, PharmD, MA, MPH, D. Juurlink, MD, PhD, G. Hawker, MD, MSc, N. Gunraj, MPH, P. Austin, PhD, D. Whelan, MD, MSc, P. Weiler, MD, MASc, P Eng. Laupacis, MD, MSc

JAMA. 2011;305(8):783-789

Population-based, nested case-control study in a cohort of women aged 68 years or older from Ontario, Canada treated with oral bisphosphonate between April 1, 2002, and March 31, 2008. Primary analysis - association between hospitalization for a subtrochanteric or femoral shaft fracture and duration of bisphosphonate exposure Secondary analysis - association of bisphosphonate use and classic intertrochanteric or femoral neck fractures

Bisphosphonates

Contraindications/Precautions Abnormalities of the esophagus which delay

esophageal emptying, such as stricture or achalasia

Inability to stand or sit upright for at least 30 minutes

Patients at increased risk of aspiration

Hypocalcemia Should be corrected prior to initiating therapy

Renal insufficiency (Not recommended if CrCl < 30-35

ml/min)

#4. How long should a patient stay on bisphosphonate treatment?

ARR = absolute risk reduction. 1. Black D et al. J Bone Miner Res. 2004;suppl 1:S45. 2. Data available on request from Merck & Co., Inc. Please specify 20650700(1)–FOS.

Cumulative Incidence of Clinical Vertebral

Fractures With 10 yrs. Alendronate

Years of Treatment Since FIT

0

2

4

6

8

10

5 6 7 8 9 10

Cu

mu

lati

ve In

cid

ence

, %

Risk Reduction1,2

55%

ALN/Placebo

ALN/ALN (Pooled)

ALN/Placebo, N: ALN/ALN, N:

437 436 428 425 419 412 404 398 392 387 662 660 651 646 638 631 626 615 606 597

5.4%

2.5%

P = 0.013

ARR 2.9%

What about a bisphosphonate “holiday”?

Reasonable to stop bisphosphonates at 5 years & follow Bone Turnover

Markers

Consider switch to teriparatide for drug holiday from bisphosphonates

FDA advisory committee,9/9/11 “… no clear evidence of benefit or harm in continuing the drugs beyond 3-5

years.”

Ott Clev Clin J Med 2011 Laster, Tanner Rheum Dis Clin of NA 2011 www.fda.gov

Bisphosphonates for Osteoporosis — Where Do We Go from Here?

The available data do not identify patients

likely to benefit from treatment beyond 3-5

years. … decisions to continue treatment must be

based on individual assessment of risks and

benefits and on patient preference.

NEJM 366:2048, 2012

OESTROGEN ANALOUGES FOR POST MENOPAUSAL WOMEN

FDA Recommendations – ET/HT

When prescribing medications for osteoporosis,

physicians should consider all non-estrogen

therapies first

When prescribing ET/HT, use smallest dose for

shortest amount of time to achieve treatment goals

Prescribe ET/HT products only when benefits

believed to outweigh risks for a specific patient

CALCITONIN

Calcitonin

FDA-approved for: Treatment of osteoporosis in women who are > 5 years postmenopausal Treatment of Paget’s disease of bone Adjunctive therapy for hypercalcemia Mechanism: Peptide composed of 32 amino acids which binds to osteoclasts and inhibits bone resorption Promotes the renal excretion of calcium, phosphate, sodium, magnesium and potassium by decreasing tubular reabsorption

Calcitonin – Clinical Efficacy

Has been shown to increase spinal bone mass and may decrease risk of vertebral fracture Conflicting data on efficacy of calcitonin at sites other than the spine Less effective than bisphosphonates in treatment of osteoporosis Beneficial, short-term effect on acute bone pain after osteoporotic fracture (vertebral)

Calcitonin – Dosing/Administration

Intranasal 200 units (1 spray) alternating nares daily Store unopened bottles in refrigerator, protect from freezing Can store open bottles at room temperature for up to 35 days Activate pump of new bottles until full spray produced (allow to reach room temperature before priming) Each bottle contains at least 30 doses IM/SQ 100 units/every other day (minimum effective dose not well-defined) Should perform skin test prior to initiating therapy Should supplement with calcium/vitamin D if dietary intake inadequate

Calcitonin – Adverse Effects

Most common:

Nasal spray: rhinitis (12%), irritation of nasal mucosa (9%), epistaxis (3.5%),

sinusitis (2.3%), back pain, arthralgia, headache

Injection: nausea (10%), flushing (2-5%)

Temporarily withdraw use of nasal spray if ulceration of nasal mucosa occurs Periodic nasal examinations recommended

Calcitonin

Contraindications Clinical allergy to calcitonin-salmon

Precautions Nasal ulcerations Tachyphylaxis (parenteral dosage forms)

Drug interactions No formal studies designed to evaluate DI

Price per month 200 units/mL (2): $42.08 200 units/ACT (3.7): $81.59

#7: Questions About Osteoporosis

What about the newest treatment: denosumab for osteoporosis ?

Prefusion osteoclast

Monoclonal antibody for Osteoporosis:RANKL-Inhibition

Adapted from Boyle et al. Nature. 2003;423:337.

CFU-M

Multinucleated osteoclast

OPG

BONE

OPG RANKL

Stromal cells

Denosumab RANK

Active Osteoclast

Cummings SR et al. N Engl J Med 2009;361:756-765

65% reduction new

spine fractures

40% reduction new

hip fractures

20% reduction new

Non-spine fractures

Denosumab 60 mg q 6 months Decreased Incidence of New Vertebral, Nonvertebral, & Hip Fractures

Densoumab

Indicated for postmenopausal osteoporosis with high fracture risk or failed, or

intolerant of other therapies

Has been given to renal impairment pts. (including ESRD) single dose, without

affecting pharmacodynamics or pharmokinetics of the drug; no safety signals

Block et al National Kidney Foundation Mtg, Orlando, FL; April 13-17, 2010

#8: Questions about Osteoporosis

Why the warning about

Proton Pump Inhibitors?

2010 FDA Warning: Proton Pump

Inhibitors and Increased Fracture Risk

Revised warning for PPI: possible increased risk of hip, wrist, &

spine fractures.

Based on 7 epidemologic studies & claims data base analysis(

no randomized trials)

Increased risk after 1-7 years of treatment ( note: OTC label for 14 days treatment)

Risk include age >50, “high dose”, longer duration

3 studies : no relation to BMD and PPI use

1 study: no fracture risk if pts. have no other risk factors

WHI: spine but not hip risk, no effect on BMD

Calcium carbonate absorption? Magnesium? Other?

www.fda.gov safety communication 5/25/10

#9: Transplantation- Induced

Osteoporosis (TIOP) 3-11% bone loss 1st yr. post transplant

14-36% increase incidence of fragility fxs.

Most fracture occur at relatively normal Bone Mineral Density: Bone Quality?

Pre-transplant: chronic disease & GCS

Post-transplant : GCS & calcineurin inhib. Controversy: cyclosporine A & tacrolimus

tacrolimus better?, may allow less GCS

Carbonare et al Transplantation 2011

#10: TIOP :Organ Specific Issues

Kidney

Bone loss: greatest in 1st 6-18 months, 4-9%

Assoc. with low estradiol & testosterone, not

always gender , age, GCS, rjxn, PTH

Fractures: higher in diabetics, more in hips,

long bones, feet than spine & ribs. Post

transplant 34% increase in hip fractures

compared to continued dialysis pts.

Treatment: increase BMD, reduce fx, adjust bisph

dose, consider Dmab

ACR recommends the following interventions in

patients taking prednisone doses of 5 mg/day or

higher for more than 3 months Calcium/vitamin D (1500mg/day, 800 IU/day)

Weekly formulations of bisphosphonate therapy

Replacement of gonadal steroids in men, if deficient

Calcitonin therapy, if bisphosphonates contraindicated or

not tolerated

Follow BMD to assess if bone loss continues

Glucocorticoid-Induced Osteoporosis –

Recommendations

HEADLINES

7.8.07

SUMMARY

REDUCING THE ‘CARE GAP’

Assess bone health in woman >50 and in men > 60.

Evaluate risk factors; evaluate BMD

Consider preventative approach to reduction of fracture risk (the way you think of

hypertension and MI and stroke)

Treat and monitor

Osteoporosis and chronic kidney disease

(CKD) are common conditions of older adults

and often occur concurrently. This follows population

trends:

(1) the older the person and the

greater the degree of osteoporosis, the greater

the risk of bone fracture2;

(2) the older the person, the higher the likelihood of havingdiabetes and high blood

pressure, the 2 most

prevalent causes of CKD

Osteoporosis has

been associated with both hypertension and

diabetes; therefore, it should come as no surprise

that older persons are likely to have both

some degree of CKD and low BMD.

Osteoporosis

is considered to result from an imbalance

between factors that promote bone production

and those that promote bone resorption, tilting

the scales toward a net increase in bone breakdown

In osteoporosis, BMD is decreased, bone microarchitecture

is disrupted, and the amount and

variety of proteins in bone are altered. Osteoporosis

is defined by the World Health Organization

in women as BMD 2.5 standard deviations

less than peak bone mass (20-year-old healthy

woman average) measured using DEXA.

CKD is associated with abnormalities in

calcium, phosphate, PTH, and vitamin D metabolism,

all of which can adversely affect bone

health. Increasingly, the broader definition of

CKD–mineral and bone disorder (CKD-MBD) is being used to describe the wide range

of

systemic mineral metabolism derangements associated

with increased morbidity and mortality in

this population.

Treatment options for women and men with

low BMD from osteoporosis have increased during

the past several decades. These options now

consist of a variety of pharmacologic therapies,

including receptor selective estrogens, androgens,

calcium and vitamin D, bisphosphonates,

PTH, fluoride, and calcitonin, as well as dietary

therapies, including phytoestrogens and soy, and

also physical therapies, including weight-bearing

or resistance exercises to improve balance,

prevent falls, and increase the mechanical strength

of the bone. Patricia et al , AJKD, 55:941-956 2010

some therapies for

osteoporosis may be relatively contraindicated in

patients with CKD

OSTEOPOROSIS AND BONE DISEASES

SPECIFIC TO THE CKD POPULATION

Bone is a complex 3-dimensional organ consisting

of organic matrix, bone cells, and mineral

salts. Factors associated with bone quality

include quantifiable factors, such as bone mass

and bone density, and qualitative factors, such

as bone geometry (shape and size), microarchitectural

features (cortical or trabecular connections),

and molecular elements (collagen type

and linkages, bone mineral composition, and

crystal orientation).

In healthy adult bone remodeling,

bone breakdown is balanced by bone formation.

However, in osteoporosis, bone mineral

and protein are normal, but the balance is

shifted toward bone breakdown, leading to

thinning of the 3-dimensional structure and

increased fragility.

CKD-MBD describes

the wide range of systemic mineral metabolism

derangements seen in people with CKD,

the term renal osteodystrophy is used to specifically

describe the various abnormalities in bone histomorphologic characteristics caused by the

characteristic disturbances in bone turnover, mineralization,

and volume

definition of CKD-MBD also includes

biochemical abnormalities and calcifications

in vascular and other soft tissues

CKD-MBD :

describes the wide range of systemic

mineral metabolism derangements, including biochemical

abnormalities and calcifications in vascular and

other soft tissues. It broadly includes diseases of bone turnover, bone mineralization, and bone volume, with

these conditions often overlapping

Adynamic bone disease :

characterized by low rates of

both bone formation and resorption and primarily a

disease of bone turnover

High-turnover disease :

characterized by increased

osteoblast and osteoclast activity with abnormal collagen

deposition, marrow fibrosis, and high rates of both

formation and resorption. This condition of bone turnover often reflects secondary hyperparathyroidism

Osteoporosis :

bone density (or bone mass) at least

2.5 standard deviations less than peak bone mass

(defined as the bone mass achieved by healthy adults

aged 18-30 y) considered to result from an imbalance between factors that promote bone production and

those that promote bone resorption, tilting the scales

toward a net increase in bone breakdown and increased

fragility

Osteomalacia :

characterized by abnormal mineralization

accompanied by a low bone formation rate resulting

in reduced bone density

Osteopenia :

bone density 1-2.5 standard deviations

less than peak bone mass (see osteoporosis)

Renal osteodystrophy :

describes the various abnormalities

in bone histomorphologic characteristics

caused by the characteristic disturbances in bone

turnover, mineralization, and volume that develop as a consequence of CKD-MBD

Decreasing kidney function progressively disrupts the relationship

among phosphorus, calcium, and their

hormonal regulators, including PTH, 1,25 dihydroxyvitamin

D,14 and the phosphaturic hormone

fibroblast growth factor 23 (FGF-23). FGF-23 is secreted mainly by osteocyctes in

response to increasing phosphate retention and

acts to increase phosphate excretion.15 Increasing

levels of FGF-23 eventually inhibit 1--

hydroxylase production in the kidney, resulting

in suppression of 1,25 dihydroxyvitamin D with

the subsequent development of hypocalcemia

and secondary hyperparathyroidism (SHPT)

The

dilemma for nephrologists is that CKD-MBD

may coexist with osteoporosis, particularly in the

elderly population in whom decreasing kidney function

is prevalent

NHANES III (Third National Health and Nutrition

Examination Survey; 1988-1994), low BMD was

much more prevalent in those with CKD than in

those with normal kidney function.16 In addition,

slightly 60% of women with a diagnosis of

osteoporosis also had CKD stage 3, and 23% had

CKD stage 4.16 Unfortunately, despite their very

different pathophysiologic states, both osteoporosisand renal osteodystrophy

independently increase

bone fragility, presenting diagnostic and therapeutic

challenges and collectively increasing the risk of

fracture at all stages of CKD

CONCLUSION

Osteoporosis is defined as a condition of impairment in bone strength due to

low bone mineral density and

poor bone quality and predisposes individuals to an increased risk of fractures.

Osteoporosis may coexist with

chronic kidney disease2mineral and bone disorder (CKD-MBD) and osteoporotic fractures occur in all stages

of CKD.

Management of osteoporosis in CKD should consider the pathophysiology of

both disorders. Diagnosis

and management of osteoporosis in patients with stages 1-3 CKD and patients

without CKD are similar,

but diagnosis and management decisions differ greatly once patients have stages 4-5 CKD. Discriminating

between osteoporosis and CKD-MBD is best accomplished with quantitative

bone histomorphometry.

Biochemical markers, especially intact parathyroid hormone and bone-specific

alkaline phosphatase, also may be helpful.

When the diagnosis of osteoporosis is established, management in stages 4-5

CKD may include

antiresorptive or anabolic agents, though evidence for efficacy is marginal in

advanced CKD.