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Parathyroid Hormone: Good, bad, but not ugly!
Richard Eastell University of Sheffield, based on invited talk by
John P. Bilezikian, MD College of Physicians and Surgeons , Columbia University
New York, NY USA
National Osteoporosis Society
Osteoporosis Conference
Birmingham, England
7-9 November 2016
The bad and the good
Bad:oToo Much Parathyroid HormoneoGood:oWhen used as an osteoanabolic
RE - Conflicts of Interest
• Lilly– Speaker fees– Consultant– Research grants
• Radius– consultant
PRIMARY HYPERPARATHYROIDISM
A common endocrine disorder characterized by incompletely regulated, chronic, excessive secretion of parathyroid hormone from one or more parathyroid glands.
Primary Hyperparathyroidism is associated with hypercalcemia and elevated levels of parathyroid hormone.
Three generational phenotypes of Primary Hyperparathyroidism
Before 1970: A disease of bone, stones, and groans
PHPT IN THE EARLY YEARS, 1929-1970PHPT IN THE EARLY YEARS, 1929-1970
Captain Martell (1918-1926)Captain Martell (1918-1926) and The lady (1970)and The lady (1970)
Pepper Pot Skull Erosion of distal clavicle
Sub-periosteal erosions brown tumours
Three generational phenotypes of Primary Hyperparathyroidism
Before 1970: A disease of bone, stones, abdominal groans and psychic moans
After 1970:A disease with primarily biochemical and densitometric signatures
The biochemical signatures of primary hyperparathyroidism in the modern era
Index Patients nl range• Calcium (mmol/L) 2.68±0.03 2.10-2.55• Phosphorus (mmol/L) 0.94±0.03 0.81-1.40• Alk Phos (IU/l) 114±4 <100• PTH (pg/ml) 121±7 10-65• 25-OH Vit D (ng/ml) 21±1 30-100• 1,25-OH2 Vit D (pg/ml) 59±2 15-60• Urinary Ca (mmol/d) 6.6+ 0.3 2.5-7.5
Silverberg, Bilezikian et al. 1989
70
80
90
100
Lumbar Spine Femoral Neck Radius
The densitometric signature of primary hyperparathyroidism in the modern era
Bone
Min
eral
Den
sity
:%
of E
xpec
ted
*
** Differs from radius,p<.05
Silverberg, Bilezikian Silverberg, Bilezikian et al.et al.
JBMR, 1989JBMR, 1989
Three generational phenotypes of Primary Hyperparathyroidism
Before 1970: A disease of bone, stones, abdominal groans and psychic moans
After 1970:A disease with primarily biochemical and densitometric signatures
After 2000: A disease that may present with a more subtle biochemical signature, namely only with PTH levels elevated, at first.
Schini M..Eastell R. NOS 2016NHYPER, normocalcaemic hyperparathyroidism
• Vitamin D deficiency– 25-hydroxyvitamin D < 75 nmol/L
• Renal insufficiency– eGFR < 60 mL/min
• Medications– Thiazide diuretics– Lithium
• Hypercalciuria• Gastrointestinal malabsorption• Other metabolic bone diseases that could be associated
with elevated PTH (e.g., Paget’s disease)
Normocalcemic primary hyperparathyroidism: what must be ruled out?
The phenotypes of Primary Hyperparathyroidism:
what form in what countries?
Symptomatic PHPT: where multichannel screening is not routinely performed and where vitamin D deficiency is common
Asymptomatic PHPT: In countries where multichannel screening is routinely performed
Normocalcemic PHPT : in countries where PTH is measured proactively in the evaluation of a suspected metabolic bone disease
Management of Asymptomatic PHPT
• Who needs surgery?• Who doesn’t need surgery?
4th International Workshop on:THE MANAGEMENT OF ASYMPTOMATIC PRIMARY
HYPERPARATHYROIDISMFlorence (Italy), September 19th – 21st, 2013
Organized byUNIVERSITÀ DEGLI STUDI DI FIRENZE, FLORENCE, ITALY
MASSACHUSETTS GENERAL HOSPITAL, HARVARD MEDICAL SCHOOL,BOSTON, MASSACHUSETTS, USA
COLLEGE OF PHYSICIANS AND SURGEONS, COLUMBIA UNIVERSITY,NEW YORK, NY, USA
andFONDAZIONE INTERNAZIONALE MENARINI
Palazzo Ximènes Panciatichi(Borgo Pinti, 68)
Maria Luisa Brandi John T. Potts, Jr. John P. BilezikianUniversità degli Studi di Firenze MGH College of Phys & Surg
Florence (Italy) Harvard Medical School Columbia University
Fondazione Internazionale MenariniVia W. Tobagi, 8
I-20068 Peschiera Borromeo (Milan, Italy)Phone: +39 02 55308110Fax: +39 02 55305739
E-mail: [email protected]:\\www.fondazione-menarini.it
Bilezikian et al. Guidelines Statement of the 4th International ConferenceOn the management of Asymptomatic PHPT. J Clin Endocrinol Metab, 2014 Eastell R et al. Diagnostic Considerations PHPT. J Clin EndocrinolMetab 2014 Silverberg et al. Clinical Presentations of PHPT. J Clin Endocrinol Metab 2014 Udelsman et al. Surgery in PHPT. J Clin Endocrinol Metab, 2014Marcocci et al. Medical Management of PHPT J Clin Endocrinol Metab, 2014
Skeletal Assessment
Renal Assessment
Traditional Aspects of Primary Hyperparathyroidism
Based upon BMD and bone biopsy data, expectations for fracture incidence in PHPT:
Vertebral sites
Non-vertebral sites
But…., Fracture Risk in Primary Hyperparathyroidism
is increased at all sites
Khosla et al,J Bone Min Res14:1700-1707, 1999
Vertebral Vertebral Distal ForearmDistal Forearm
Rib Rib All All
Increased Fracture Risk at all sites:Confirmatory evidence
High Resolution peripheral Computed Tomography (Hansen et al. JBMR, 2012; Stein, Silva et al. JBMR, 2013)
Trabecular Bone Score (Silva et al. J Clin Endocrinol Metab, 2013)
Moving the field forward with a “new” hypothesis
Primary hyperparathyroidism, even when presenting as an asymptomatic disorder, is characterized by compromised cortical and trabecular compartments and increased fracture risk
Skeletal Assessmen
t Renal
Assessment
Traditional Aspects of Primary Hyperparathyroidism
Emergence of the Modern Clinical Profile of
Primary HyperparathyroidismCope et al.’30-’65
Mallette et al. ‘65-’74
Silverberg et al. ‘84-’00
Cusano et al.’10-’12
Nephrolithiasis 57% 37% 17% 14.3%
Hypercalciuria Not reported
40% 39% 29%
Overt Skeletal Disease
23% 14% 1.4% <1%
Asymptomatic 0.6% 22% 80% >80%
New data and reinterpretation of old data• Skeletal involvement more evident in PHPT when
the eGFR < 60 cc/min (Walker et al, 2012)• A 24-hour urine for analysis of biochemical stone
risk factors (Ca, P, SO4, uric acid etc) is predictive of stones in PHPT (Peacock, 2013)
• Kidney stones can be detected by non-invasive imaging (e.g. X-ray, ultrasound, CT)
• Kidney stones are still the most common complication of PHPT
Neuro-cognitiv
eCardio-
vascular
Other Aspects of Primary Hyperparathyroidism
Gastro-intestinal
Vitamin D
4th International Workshop on:THE MANAGEMENT OF ASYMPTOMATIC PRIMARY
HYPERPARATHYROIDISMFlorence (Italy), September 19th – 21st, 2013
Organized byUNIVERSITÀ DEGLI STUDI DI FIRENZE, FLORENCE, ITALY
MASSACHUSETTS GENERAL HOSPITAL, HARVARD MEDICAL SCHOOL,BOSTON, MASSACHUSETTS, USA
COLLEGE OF PHYSICIANS AND SURGEONS, COLUMBIA UNIVERSITY,NEW YORK, NY, USA
andFONDAZIONE INTERNAZIONALE MENARINI
Palazzo Ximènes Panciatichi(Borgo Pinti, 68)
Maria Luisa Brandi John T. Potts, Jr. John P. BilezikianUniversità degli Studi di Firenze MGH College of Phys & Surg
Florence (Italy) Harvard Medical School Columbia University
Fondazione Internazionale MenariniVia W. Tobagi, 8
I-20068 Peschiera Borromeo (Milan, Italy)Phone: +39 02 55308110Fax: +39 02 55305739
E-mail: [email protected]:\\www.fondazione-menarini.it
Neurocognitive and CVsystems:Data are not secure enough for
decisions on the surgical management of PHPT
(Bilezikian et al. JCEM, 2014)
Neuro-cognitiv
eCardio-
vascular
Other Aspects of Primary Hyperparathyroidism
Gastro-intestinal
Vitamin D
PTH Levels as function of Vitamin D status (Stein et al. JCEM, 2011)
Mean ±SD 20 ng/mL = 50 nmol/L
4th International Workshop on:THE MANAGEMENT OF ASYMPTOMATIC PRIMARY
HYPERPARATHYROIDISMFlorence (Italy), September 19th – 21st, 2013
Organized byUNIVERSITÀ DEGLI STUDI DI FIRENZE, FLORENCE, ITALY
MASSACHUSETTS GENERAL HOSPITAL, HARVARD MEDICAL SCHOOL,BOSTON, MASSACHUSETTS, USA
COLLEGE OF PHYSICIANS AND SURGEONS, COLUMBIA UNIVERSITY,NEW YORK, NY, USA
andFONDAZIONE INTERNAZIONALE MENARINI
Palazzo Ximènes Panciatichi(Borgo Pinti, 68)
Maria Luisa Brandi John T. Potts, Jr. John P. BilezikianUniversità degli Studi di Firenze MGH College of Phys & Surg
Florence (Italy) Harvard Medical School Columbia University
Fondazione Internazionale MenariniVia W. Tobagi, 8
I-20068 Peschiera Borromeo (Milan, Italy)Phone: +39 02 55308110Fax: +39 02 55305739
E-mail: [email protected]:\\www.fondazione-menarini.it
Nutritional elements:Vitamin D sufficiency (25-OH D levels > 50 nmol/L are
recommended)*Calcium intake should follow
national guidelines(Bilezikian et al. JCEM, 2014) Some experts recommend > 75 nmol/L
Pharmacological Approaches to PHPTAgent Serum
calciumBone Mineral Density
PTH
Estrogen1
Raloxifene2
Bisphosphonate3 (Alendronate)
Cinacalcet4
Cinacalcet andBisphosphonate5
1Marcus et al, 1991; Marcus et al, 1991; 2Rubin et al, 2005, Rubin et al, 2005, 3Khan et al.2004, Khan et al.2004, 4Peacock et al, 2005, 2009, Peacock et al, 2005, 2009, 5Faggiano et al, 2011Faggiano et al, 2011
2014 Guidelines for Surgery in Asymptomatic Primary Hyperparathyroidism (Bilezikian et al. JCEM, 2014)
Recommended Index
3rd Int’l Workshop (Bilezikian et al. JCEM 2009)
4th Int’l Workshop (Bilezikian et al., 2014)
Serum calcium(above normal) >0.25 mmol/L > 0.25 mmol/L
Skeletal DXA: T-Score <-2.5 at any site; any fragility fracture
DXA: T-Score < -2.5 at any site; Vert Fx by X-ray or VFA
RenaleGFR< 60 mL/min24 hr urine: Not recommended
eGFR< 60 mL/minStone by X-ray, CT, or ultrasoundUrinary calcium: >10 mmol/d plus other urinary biochemical indices of increased stone risk
Age <50 < 50
2014 Guidelines for Monitoring in Asymptomatic Primary Hyperparathyroidism
(Bilezikian et al. JCEM, 2014)
Index 3rd Int’l Workshop (Bilezikian et al. JCEM, 2009)
4th Int’l Workshop (Bilezikian et al, JCEM, 2014)
Serum Calcium Annually Annually
Skeletal DXA: Every 1 or 2 years
DXA: Every 1 or 2 years; CT or VFA if clinically indicated
Renal Clcr-Annually Clcr-Annually; stone risk profile if clinically indicatedAbdominal imaging (X-ray, CT, or ultrasound) if clinically indicated
The bad and the good
Bad:oToo Much Parathyroid HormoneoGood:oWhen used as an osteoanabolic
The “Holy Grail” of osteoporosis therapyWhat the antiresorptives
don’t do…
AnabolicDaily(low dose)
CatabolicContinuous (high dose)
EFFECTMODE
The clue to discovering that PTH, under specifiedcircumstances, can serve as an osteoananabolic
treatment for osteoporosis
Dobnig H, et al. Endocrinology 1997;138:4607-12.
BADGOOD
Cellular Mechanisms
PTH treatment initially stimulates bone formation PTH treatment initially stimulates bone formation directly with or without the involvement of the bone directly with or without the involvement of the bone remodeling unitremodeling unit
PTH as an Anabolic Agent for Bone:A Kinetic Model
Months
Inde
x of
Bon
e Tu
rnov
er
Peak
Bone formation markers
Bone resorptionmarkers
“Anabolic Window”
Effect of Teriparatide on Incidence of Vertebraland Non-Vertebral Fractures in
Postmenopausal Women with Osteoporosis
Neer RM, et al. N Engl J Med. 2001;344:1434-41
0
2
4
6
8
10
12
14
16
18
20Non-vertebral fractures
Patients (%) with fracture
P< 0.01
53%
20 g PTH0
2
4
6
8
10
12
14
16
18
20New vertebral fracture
Patients (%) with fracture
P< 0.01
65%
20 g PTH PlaceboPlacebo
3-D µCT Images of iliac crest biopsies before and after Teriparatide
Placebo Teriparatide
Emergence of a new osteoanabolicAbaloparatide, an analogue of PTHrP
Hattersley G, Bilezikian JP, Kumar P et al. The Endocrine Society 94th Annual Mtg Houston, 2012
39
22 30 34100% hPTHrP
38% hPTHrP
Teriparatide
hPTHrP1-34
Abaloparatide100% hPTHrP 38% hPTHrP
22 34
based on amino acid replacements between residues 22-34
Taking advantage of basic mechanisms to develop a PTH/PTHrP
analogue that has greater osteoanabolic activity
Hypothesis:
Abaloparatide will bind more selectively bind to the transient RG configuration of the PTH/PTRrP receptor
The binding of ABL, PTH (1–34), PTHrP (1–36) and LA-PTH to two distinct PTHR1 conformations RG (A) and R0 (B)The binding of ABL, PTH (1–34), PTHrP (1–36) and LA-PTH to two distinct PTHR1 conformations RG (A) and R0 (B) was assessed by competition methods in membranes prepared from GP-2.3 cells stably expressing the PTHR1.was assessed by competition methods in membranes prepared from GP-2.3 cells stably expressing the PTHR1.
RG reactions used 125I-M-PTH (1–15) as tracer radioligand, which binds selectively to the G protein–coupled receptor RG reactions used 125I-M-PTH (1–15) as tracer radioligand, which binds selectively to the G protein–coupled receptor conformation (RG). R0 reactions used 25I-PTH (1–34) as tracer radioligand and contained an excess concentration conformation (RG). R0 reactions used 25I-PTH (1–34) as tracer radioligand and contained an excess concentration
(1 × 10−5 M) of GTPγS, which enriches for the G protein–uncoupled receptor conformation (R0). Data are means (± SEM) (1 × 10−5 M) of GTPγS, which enriches for the G protein–uncoupled receptor conformation (R0). Data are means (± SEM) of six experiments, each performed in duplicate. Curve fitting parameters are reported in Table 1.of six experiments, each performed in duplicate. Curve fitting parameters are reported in Table 1.
Hattersley, G et al. Endocrinology 2016, 157, 141-149.
Abaloparatide binding to the PTH receptor differs from PTH binding
Update on Abaloparatide
• International Phase 3 trial ended, September, 2014• Results made available, December, 2014• Presented by Miller et al, Endocrine Society, March,
2015, 2016• Clinical Trial Results JAMA (2016) 1
1 Miller PD, et al. JAMA. 2016 Aug 16;316(7):722-33.
Phase 3 Trial Design of Abaloparatide Clinical Trial
Placebo
Abaloparatide 80 mcg Daily SC
Teriparatide 20 mcg Daily SC
Months 6 12 18
N = 2463
Miller et al, Endo Soc 3-15Miller et al, Endo Soc 3-15
P1NPP1NPCTXCTX
Months Months
* **
* *
*
**
**
*
Perc
ent C
hang
e fr
om B
asel
ine
Perc
ent C
hang
e fr
om B
asel
ine
Perc
ent C
hang
e fr
om B
asel
ine
Perc
ent C
hang
e fr
om B
asel
ine
*p < 0.0001 vs placebo#p < 0.01 vs teriparatide
# ##
##
#
Teriparatide
-46% -12%-56%
-69%
-28%
-33%
Changes in Bone Turnover Markers:Abaloparatide vs. Teriparatide vs. Placebo
(Miller et al. Endo Soc 3-15)
“Anabolic window”
PTH/PTHrP analogues that stimulate bone formation to a greater extent than bone
resorption: a time dependent model
Months
Inde
x of
Bon
e Tu
rnov
er
Peak
Bone Formation Markers
Bone ResorptionMarkers
Teriparatide
Lumbar Spine BMD
% C
hang
e fr
om B
asel
ine
Months
#p < 0.01 vs TP
#
#
Changes in BMD at the Spine and Reduction in New Vertebral Fractures: All 3 Groups
(Miller et al. Endo Soc 3-15)
Abalopara
tide
teripara
tide
Changes in BMD at Non-Vertebral Sites and NVF Risk Reduction: All 3 Groups (Miller et al. Endo Soc 3-15)Total Hip BMD
% C
hang
e fr
om B
asel
ine
Months
#
#^#p < 0.0001 vs TP
p̂ = 0.0003 vs TP
Femoral Neck BMD
% C
hang
e fr
om B
asel
ine
Months
#
#
@#p < 0.0001 vs TP@p = 0.0016 vs TP
Life with PTH
• Too much (Primary Hyperparathyroidism)- not good
• When used in just the right way: an important osteoanabolic therapy for osteoporosis
THANK YOU!