Pregnancy associated osteoporosis and fractures

Ashok K Bhalla Royal National Hospital for Rheumatic Diseases,

Bath

Pregnancy Associated Bone Disorders

• Pregnancy has number of consequences to bone/skeleton.

• Include vertebral fractures, occasionally hip, termed pregnancy and lactation associated osteoporosis.

• Transient osteoporosis of pregnancy• Osteonecrosis/ avascular necrosis• Stress fractures.

Pregnancy Associated Osteoporosis

• Rare for fragility fractures to occur during pregnancy, post-partum, breastfeeding

• Cause not understood: some pre-existing low bone density with added mechanical & metabolic stress, but others normal BMD.

• Most studies found no association between parity or breastfeeding and osteoporosis and fracture in postmenopausal women in USA/Europe.

Skeleton and Pregnancy 1GUT

• 20-30 g calcium transferred to foetus by term; 80% in 3rd trimester• when woman provides 300-500mg calcium /day in final 6 weeks.• Total Ca falls due to decrease albumin but ionised Ca constant.

• Achieved by increase in absorption of calcium in gut from week 12.• Mechanism unknown but calcitriol likely involved.• Total calcitriol increases 2-3x early throughout.• But free calcitriol only increased in 3rd trimester.• Increase in calcitriol not due to PTH; PTH levels fall.• Most likely renal 1-alpha hydroxylase upregulated by many factors,• including PTH-rP, placental lactogen, prolactin.• Urine Ca excretion increases reflecting increased intestinal

absorption

Skeleton and Pregnancy 2Bone

Skeletal Ca available as well. Bone histomorphometry showed increased bone resorption in 15 women elective termination cf to contro

Bone resorption increases but PTH falls to low/ normal levels.Bone resorption markers increasing early from 26 weeks. Formation markers decrease below pre-pregnancy rising to normal or above before term.

Skeleton and Pregnancy 3Bone

• PTH-rP may be responsible, secreted from breasts and placenta.

• IGF-1 possible role in bone turnover during pregnancy.• Bone marker studies confounding variables: increased

degradation, increased GFR, no pre-pregnancy levels, placental, foetal and uterine contribution to markers

BMD Changes in Pregnancy (1)

Largest prospective study ( Moller 2012) of 92 women enrolled up to 8 months prior to planned pregnancy.

DXA baseline and 15 ,129, 280 days postpartum compared with controls. All women went on to breast feed.

BMD decreased: LS by 1.8%, 3.2% TH, 2.4% whole body,4.2% distal radius between pre- and post- pregnancy.

BMD decreased further during breast feeding.

BMD Changes in Pregnancy (2)

3 groups breast feeding: cat.1<4mnths; cat.2 4-9mths; cat 3 >9mths.

At 4 months post-delivery BMD decreased in categories 2,3 by 1% WB; 5%LS; 2%TH.Between 4 to 9 mths LS BMD increased all categories.

At 9 mths cat.1&2 had similar LS BMD to controls while continued breast feeding lead to further loss at LS and TH.

Despite this, breastfeeding >4mths lead to lower BMD compared to pre-pregnancy.31 women had BMD at 19mths ; none breastfeeding.74% had regained pre-pregnancy BMD

Mean percentage change from baseline in total bodyand regional BMD after pregnancy (Naylor JBMR 200)

Breastfeeding 1

• Daily loss calcium in milk 210 mg• But gut calcium absorption and calcitriol levels

return to normal• Need met by resorption of bone via “brain-bone-

breast circuit”• Involves prolactin, which stimulates milk production and

reduces pituitary hormones causing low oestrogen• This leads to increased bone turnover• PTH-rP from breast also stimulates bone resorption

Kovacs, Ralston OI 2015

Breast-Brain-Bone Circuit

CALCIUMINTAKE

NORMAL LACTATIONPREGNANCYCALCIUMINTAKE

CALCIUMINTAKE

SERUM Ca2 SERUM Ca2+ SERUM Ca2+

URINE URINE

Case Twin Pregnancy

• 36 female• 2 months after birth of twins back pain lifting

from cot• Spine curvature • MRI confirmed wedge fractures

Management

• BMD LS T -4.2 Z -4.1• Other lab tests normal• Further fractures• Risedronate and Ca plus Vitamin D• Repeat BMD 2 y later:• LS T-2.4 Z-2.3 increase of 32%

• FN increase of 10%

Case 2 ? Underlying cause

• 32 years Living in the UK since 2007• No significant past medical history

• Non-smoker and no alcohol• No history of back pain• No family history of osteoporosis• Menarche aged 15• Reasonable diet

Case 2 -Underlying cause

• Gave birth to her first baby in July 2008• Breast feeding when• November 2008

– Presented to GP with sudden onset low back pain, like an “electric shock”.

– No radiation– No bowel/bladder disturbance– No preceding trauma– Treated with analgesia

RESULTS

• X-rays showed vertebral fractures at T6, T8, T9, T10 and L1, L2, L4.

• Lumbar vertebral fractures confirmed by MRI.

• Bloods– Normal U+E’s / LFT’s / CRP / Viscosity / FBC / TSH /

Anti-TTG.– Calcium borderline low with normal phosphate and

alkaline phosphatase– Vitamin D 9.1 nmol/L, PTH 13.8 pmol/L (1.6-6.9)

BMD

• Next seen April 2010.

• Vitamin D normal

T-score2009

Z-score2009

Lumbar spine

-3.7 -3.4

Femoral neck

-2.2 -2.1

Total hip -2.5 -2.4

T-score 2010

Z-score 2010

-2.5 -2.3

-1.9 -1.8

-2.4 -2.4

January 2011

• Two months post partum• Low back pain significantly worse during

third trimester and post partum period.• Struggling with ADL’s.• Tender thoracic and lumbar spine with

pain on thoracic rotation.• Repeat X-rays requested.

Feb 2009 Jan 2011

MRI 2009/2011

T-score 2009

Z-score 2009

T-score 2010

Z-score 2010

T-score 2011

Z-score 2011

L-spine

-3.7 -3.4 -2.5 -2.3 -2.5 -2.5

Fem neck

-2.2 -2.1 -1.9 -1.8 -1.4 -1.3

Tot. hip

-2.5 -2.4 -2.4 -2.4 -2.0 -1.9

Another case ? cause

• Age 4 fracture scapula, humerus fall from standing height

• Age 5 fracture right clavicle• Age 15 possibly subluxed hip• Age 19 lifting her new baby, acute onset back pain

fractures T6 T8• Slim, would not allow back to be approached• Labs including bone biopsy normal• Inpatient rehabilitation, pain control

Management

• Risedronate

• Genetic study COL1A2 gene mutation consistent with Osteogenesis Imperfecta

Causes of pregnancy associated osteoporosis

• Investigate for secondary causes.• Genetic causes is some cases eg OI, inactivating

mutations in LRP5 (JCEM 2014, JBMR 1015).• Other RF: anorexia, petite frame, heparin, anticonvulsants,

depot medroxyprogesterone.• Case reports occurring with LMWHs: enoxaparin (Ozdemir

OI 2015)• Dunne et al (1993) identified 29 women with pregnancy

related osteoporosis.• Significantly higher prevalence of adult related fractures

occurring at an earlier age in the mothers of affected subjects when compared to controls.

Are usual anti-osteoporosis drugs indicated?

Bisphosphonates in pregnancy• In animal studies

– Bisphosphonates have been shown to cross the placenta– Resultant decrease in fetal weight and bone growth

• In humans– Case reports and case series identify 51 pregnancies with a

history of bisphosphonate exposure at the time of pregnancy or within the preceding 3 months.

– No definite measureable risk identified to embryo or foetus.– Should measure foetal serum calcium levels in the early days

post-birth.

• Djokanovic et al. Does treatment with bisphosphonatesendanger the human pregnancy? J Obstet Gynaecol Can

2008;30(12):1146–1148.

Bisphosphonates and pregnancy related osteoporosis

• Hellmeyer et al (2007) report the case of a 28 year old with vertebral fractures 2 months post partum.

• Treated for 2 years with I.V. Ibandronate (2mg every 3 months) and calcium and Vit. D.

• Noted “rapid” improvement.• Concluded that in cases of multiple fractures I.V.

bisphosphonates lead to a decrease in symptoms and fracture risk with an increase in BMD.

• Hellmeyer at al. Exp Clin Endocrinol Diabetes. 2007 Feb;115(2):139-42.

Bisphosphonates and pregnancy related osteoporosis

• Reid 2006 (OI) 11 pts.• 9 pts received BP• 5 elected BP within 1 year• BMD increased by 23% at 2 yrs.• BMD increased in spine by 17% in those treated with

BP within 2 yrs compared to 2% not treated within 2yrs.• 5 subsequent pregnancy, 1 further fracture not on BP• 2pts with fractures but not during pregnancy

Can the skeleton recover without specific treatment?

• Philips et al. (1999) assessed 13 women with pregnancy associated osteoporosis.

• 8 presented with back pain and 5 with hip pain.• Mean lumbar Z-score in the back pain group was -3.3 (range -2.2 - -

4.7)• Over f/u of up to 8 years, BMD increased towards the lower end of

normal.• Concluded that in those with idiopathic osteoporosis BMD should

improve post partum without specific intervention.

• Phillips et al. Pregnancy Associated Osteoporosis: Does the Skeleton Recover? Osteo Int. 1999;11(5):449-454.

Teriparatide and pregnancy related osteoporosis

• Stumpf et al. (2007) report the case of a 32 year old with thoracic and lumbar fractures.

• Previous history of a pulmonary embolus requiring LMWH.

• Treated with 6 months of teriparatide and had a 42% improvement in spinal BMD.

• Stumpf et al.. Adv Med Sc 2007;52:94-97.

Transient Osteoporosis of Pregnancy• TOP rare first described. by Curtiss and Kincaid in 1959.• Usually in 3rd trimester with pain on activity and reduced

hip movements- xray osteopenia, MRI diffuse bone oedema with increased T2 and decreased T1 signal intensity.

• Termed transient osteoporosis of hip.• Sometimes both hips affected.• May affect other bones: wrist, knee, ankle, elbow.• Can evolve into transient migratory osteoporosis.• Rx conservative, decrease wt bearing, settles within

months• Occ use of BP in TOP

Transient OP of Hips Knees

Transient OP of Hips Knees

Osteonecrosis (ON)-Avascular Necrosis

• ON of femoral head rare, unknown aetiology.• Weight gain, endogenous glucocorticoid production,

hypercoagulable.• Hip pain to groin or thigh.• Montella (JBJS 1999) 13 cases , all left side and 4

bilateral; 11 primigravid, 2nd or 3rd trimester.• Small body size but relatively large wt gain.• Delayed diagnosis- mistaken for TOH.• Progressive to collapse and DJD• Treatments include osteotomy, core decompression,

grafts.

ONJ HIP 1

Stress Fractures

• Sacral stress fractures reported as case reports.• Of 14 reported, 13 postpartum.• Pain in buttock, hip and low back, worse on sitting,

walking, better resting.• Plain xray usually normal, MRI required for diagnosis.• Treatment is conservative: rest, limit activity,

Conclusions

• Uncommon condition but probably under-diagnosed.

• Cause still unclear.• No real evidence base for any treatments

other than case reports. • BMD will improve spontaneously in

idiopathic cases but maybe more quickly with intervention.

• It may recur but uncommon.