REVIEW URRENT C OPINION

Osteoporosis presenting in pregnancy, puerperium, and lactation Christopher S. Kovacs

Purpose of review To describe our current state of knowledge about the pathophysiology, incidence, and treatment of osteoporosis that presents during pregnancy, puerperium, and lactation. Recent findings When vertebral fractures occur in pregnant or lactating women, it is usually unknown whether the skeleton was normal before pregnancy. Maternal adaptations increase bone resorption modestly during pregnancy but markedly during lactation. The net bone loss may occasionally precipitate fractures, especially in women who have underlying low bone mass or skeletal fragility prior to pregnancy. Bone mass and strength are normally restored postweaning. Transient osteoporosis of the hip is a sporadic disorder localized to one or both femoral heads; it is not due to generalized skeletal resorption. Anecdotal reports have used bisphosphonates, strontium ranelate, teriparatide, or vertebroplasty/kyphoplasty to treat postpartum vertebral fractures, but it is unclear whether these therapies had any added benefit over the spontaneous skeletal recovery that normally occurs after weaning. Summary These relatively rare fragility fractures result from multifactorial causes, including skeletal disorders that precede pregnancy, and structural and metabolic stresses that can compromise skeletal strength during pregnancy and lactation. Further study is needed to determine when pharmacological or surgical therapy is warranted instead of conservative or expectant management. Keywords lactation, osteoporosis, parathyroid hormone-related protein, pregnancy, transient osteoporosis of the hip

INTRODUCTION Women rarely develop fragility fractures of the spine or hip during late pregnancy or puerperium; the vertebral fracture risk increases further in women who breastfeed. The purpose of this article is to review our current state of knowledge about the pathophysiology, incidence, and treatment of osteoporosis that presents during the reproductive cycle.

SKELETAL PHYSIOLOGY DURING PREGNANCY During the third trimester, women provide most of the 30 g of calcium present in the fetal skeleton at birth [1,2]. The rate of intestinal calcium absorption doubles in order to meet the demand for calcium, but modest skeletal resorption also occurs [3,4]. Increased resorption was present on first-trimester bone biopsies [5], bone resorption markers increase during pregnancy [3,4], and 0–5% decreases in www.co-endocrinology.com

whole body and lumbar spine bone mineral density (BMD) were found when paired dual-energy X-ray absorptiometry (DXA) measurements were done prior to planned pregnancy and several weeks after delivery [3,4]. Serial ultrasound of the heel has also suggested that some bone loss may occur during pregnancy [6]. But pregnancy can benefit bone mass, as shown by a 15% gain in BMD in an osteoporotic woman [7]. Placenta and breast secrete parathyroid hormone-related protein (PTHrP), which reaches the maternal circulation and may stimulate bone turnover [8 ]. &

Faculty of Medicine – Endocrinology, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada Correspondence to Dr Christopher S. Kovacs, MD, Health Sciences Centre, 300 Prince Philip Drive, St. John’s, NL A1B 3V6, Canada. Tel: +1 709 777 6881; fax: +1 709 777 8049; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2014, 21:468–475 DOI:10.1097/MED.0000000000000102 Volume 21  Number 6  December 2014

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KEY POINTS  Osteoporotic fractures rarely occur in association with pregnancy and lactation.

i GnRH

 Unrecognized skeletal fragility before pregnancy may be unmasked by structural and metabolic demands placed on the skeleton during pregnancy and lactation.

OT PRL

i LH, i FSH i E2, i PROG

 Significant bone loss normally occurs during lactation without causing skeletal fragility.

Ca2+

CT

Ca2+

 The skeleton typically restores itself after weaning such that parity and lactation do not increase the long-term risk of fracture.

Ca2+ PTHrP

 The clinician should consider withholding pharmacological therapy until the extent of normal postweaning skeletal recovery can be evaluated.

SKELETAL PHYSIOLOGY DURING LACTATION Lactating women have even greater daily losses of calcium to produce milk, and skeletal resorption provides much of it [3,4]. Bone resorption is programmed by coordinated regulation within a brain– breast–bone circuit (Fig. 1) [9,10]. Suckling and prolactin suppress the hypothalamic–pituitary– ovarian axis, thereby resulting in low estradiol and progesterone. In turn, low estradiol upregulates receptor activator of nuclear factor kB ligand (RANKL) and downregulates osteoprotegerin release by osteoblasts, which increase the formation, recruitment, and activity of osteoclasts [11]. Suckling [12,13], prolactin [14–17], low estradiol [18], calcium-sensing receptor [19,20], and other factors stimulate mammary tissue to produce PTHrP, which stimulates bone resorption [8 ]. Calcitonin is also produced by lactating breasts and may reduce the calcium content of milk, PTHrP synthesis by mammary tissue, prolactin release by pituitary, and the formation and activity of osteoclasts [21,22 ]. Oxytocin stimulates milk ejection, but its local expression and receptor within bone may mean that it directly modulates bone turnover [23,24]. Serotonin may be a mediator of PTHrP’s effects during lactation [25,26 ]. Increased circulating PTHrP and low estradiol synergize to increase bone resorption [3]. PTHrP may be more important because deletion of its gene from mammary tissue reduced lactational bone loss in mice [27], in which isolated estradiol deficiency from ovariectomy leads to relatively slow loss of bone [3,28]. By histomorphometry, lactating rodents have increased osteoclast-mediated bone resorption and resorption of pericellular matrix by &

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FIGURE 1. Brain–breast–bone circuit. Suckling and prolactin both inhibit the hypothalamic gonadotropinreleasing hormone pulse center, which in turn suppresses the gonadotropins (luteinizing hormone and follicle-stimulating hormone), leading to low levels of the ovarian sex steroids (estradiol and progesterone). Prolactin may also have direct effects on its receptor in bone cells. PTHrP production and release from the breast are controlled by several factors, including suckling, prolactin, low estradiol, and the calcium receptor. PTHrP enters the bloodstream and combines with systemically low estradiol levels to markedly upregulate bone resorption. Increased bone resorption releases calcium and phosphate into the blood stream, which then reaches the breast ducts and is actively pumped into the breast milk. PTHrP also passes into milk at high concentrations, but whether swallowed PTHrP plays a role in regulating calcium physiology of the neonate is unknown. In addition to stimulating milk ejection, oxytocin may directly affect osteoblast and osteoclast function (dashed line). Calcitonin may inhibit skeletal responsiveness to PTHrP and low estradiol given that mice lacking calcitonin lose twice the amount of bone during lactation as normal mice. CT, calcitonin; E2, estradiol; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; OT, Oxytocin; PRL, prolactin, PROG, progesterone; PTHrP parathyroid hormone-related protein. Adapted with permission from [9]; 2005 Springer Science and Business Media B.V.

osteocytes (osteocytic osteolysis) [3,29]. Circulating bone resorption markers increase substantially, progressive loss of BMD occurs on serial DXA and micro-computed tomography (mCT), and ash weight and mineral content are reduced 20–30% when lactation ceases [3,30,31 ]. Greater losses are provoked by a calcium-restricted diet, large litters, or

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genetic deletion of calcitonin [3,21]. Conversely, a calcium-rich diet blunts bone loss during lactation [32,33]. Women have significantly increased bone resorption during lactation, as confirmed by bone resorption markers, and longitudinal DXA studies that found 5–10% losses of trabecular BMD over 3–6 months of lactation, with smaller losses at cortical sites [3,34]. Lactating adolescents lost 10–15% from baseline [35,36]. The normal rate of BMD loss during lactation approximates 1–3% per month, whereas more than 1–2% per year is considered rapid after menopause. Intestinal calcium absorption is normal, which underscores that increased skeletal resorption supplies much of the calcium in milk [3,4]. Randomized trials and cohort studies found that bone loss during lactation is not reduced by increased calcium intake [37–40]. Breast milk output correlates with BMD loss [41] and predicts that women nursing twins will lose even more. PTHrP’s importance during human lactation has been implicated by the substantial loss of BMD during lactation as compared with smaller losses during 6 months of estradiol deficiency induced by gonadotropin-releasing hormone analogs [3], or the smaller annual losses of BMD that occur after menopause. Higher plasma PTHrP significantly predicted loss of BMD after controlling for low estradiol, PTH, and breastfeeding status [42].

SKELETAL PHYSIOLOGY AFTER LACTATION In animals, osteoclasts undergo widespread apoptosis at weaning, although osteoblast numbers increase markedly [22 ,43,44]; the resulting bone formation restores the mineral content [3,21,44]. Osteocytes also induce bone formation in their surrounding lacunae [45,46]. Bone biomarkers confirm that bone resorption is suppressed, whereas bone formation is upregulated [3,30,44]. Rodents restore BMD within 2–3 weeks after weaning as assessed by DXA [21,44]. In contrast, mCT has shown that the speed and completeness of recovery vary by skeletal site; the vertebrae recover completely, whereas the long bones have incomplete recovery of trabecular bone [47]. However, cross-sectional diameters and volumes of the long bones increase during pregnancy and lactation [21,48,49]. Additional studies found that PTH, PTHrP, calcitonin, vitamin D, and vitamin D receptor are not required for skeletal recovery to be achieved after lactation [3,21,30,31 ,50]. In women, longitudinal DXA studies found that the skeleton is typically restored to the prior BMD level within 6–12 months after weaning [3,4]. As in &

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rodents, the speed and magnitude of recovery may vary between skeletal sites, and the trabecular content of the long bones may be incompletely restored [3,34,40,51]. However, cross-sectional diameters of the femur and radius increase [52,53], which offsets the decline in strength that loss of trabecular architecture would otherwise cause.

LONG-TERM SKELETAL EFFECTS OF NORMAL PREGNANCY AND LACTATION Several dozen large epidemiological studies have shown that parity and lactation do not increase the risk of low BMD, osteoporosis, or fracture in the long term [3,34]; nor are these risk factors for fracture in FRAX, the fracture risk calculator developed by the World Health Organization [54]. Multiple large studies have even shown a protective effect of parity or lactation on the subsequent risk of osteoporosis [52,55–66,67 ,68 ,69,70]. Teenaged pregnancy and lactation do not reduce peak bone mass because the BMD of women aged 20–25 years was unaffected if they had been pregnant or breastfed as adolescents [71]. &

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CLINICAL PRESENTATIONS OF FRACTURES In their classic 1948 report, Albright and Reifenstein [72] described two young women who had idiopathic osteoporosis caused or worsened by pregnancy. But this disorder has evidently been occurring for five millennia because low BMD and vertebral fractures are present in Egyptian mummies and other archaeological examples of 16 to 30-yearold female skeletons [73 ]. The exact incidence of vertebral or hip fractures during pregnancy, puerperium, and lactation is unknown. However, such fractures are uncommon, with most gynecologists and family physicians being aware of one or two affected patients in their practice. Fractures at other sites (e.g., wrist, ankle) may not prompt concern that the reproductive cycle was a causative factor. Three main, but overlapping, presentations of osteoporosis in the setting of recent pregnancy are discussed in the following sections. &

PATHOPHYSIOLOGY OF VERTEBRAL FRACTURES DURING PREGNANCY Most women who fracture during pregnancy or in the puerperium are otherwise healthy. The BMD prior to pregnancy is unknown, although at presentation, it is usually low [74–77]. Consequently, it remains unknown whether low bone mass or an Volume 21  Number 6  December 2014

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accelerated bone resorptive state preceded pregnancy, or whether substantial bone loss occurred during pregnancy. Serum calcium, phosphorus, and calciotropic hormone levels are generally normal [75,76]. The increased weight-bearing and lordotic posture of pregnancy may precipitate thoracic or lumbar fractures in women who have low bone mass or skeletal fragility prior to pregnancy. Genetic or familial disorders may be found, such as mild osteogenesis imperfecta, inactivating mutations in low-density lipoprotein receptor-related protein 5 (LRP5) [78 ,79 ], hypercalciuria, idiopathic osteoporosis [80], premature ovarian failure [81]. Other factors may include anorexia, low body weight, petite frame, oligoamenorrhea, lactose intolerance, low calcium intake, severe vitamin D deficiency, heparin, oral glucocorticoids, gonadotropin-releasing hormone analogs, depot medroxyprogesterone acetate, and certain anticonvulsants [3,75,80,82 ,83–85]. Inactivity during pregnancy from bed rest or hospitalization causes bone loss [86 ]. Some cases may represent chance occurrences without pathophysiological links to pregnancy. Conceivably, some women may experience accelerated bone loss during pregnancy. Hypercalcemia has occurred during pregnancy because of increased production of PTHrP from the breasts (resolving after mammoplasty) [87–90], or from the placenta (resolving immediately after delivery) [91]. Bone resorption must have been increased in order to cause hypercalcemia, and so these cases support that significant PTHrP-mediated bone loss can occur during pregnancy. Among five women who presented with symptomatic osteoporosis during a first pregnancy, there was no clinically or radiographically evident worsening during a subsequent pregnancy or multiple years of follow-up [92]. Women who fracture during pregnancy are more likely to have a maternal family history of severe osteoporosis [85]. The few published bone biopsies have typically revealed only mild osteoporosis [74,75,93]. Fractures typically occur in a first pregnancy, usually do not recur, and parity does not increase the risk [76,77,85,94]. Taken together, these findings suggest that the osteoporosis preceded pregnancy but also that a reversible cause in the first pregnancy was subsequently corrected (e.g., poor nutrition). &&

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PATHOPHYSIOLOGY OF TRANSIENT OSTEOPOROSIS OF THE HIP Focal, transient osteoporosis of the hip is a rare disorder localized to one or both femoral heads [95–98,99 ]. Women present during the third &&

trimester or early postpartum with pain in one or both hips, limp, or hip fracture(s) [96,97,100–103]. The affected femoral head and neck are radiolucent on radiographs [95,99 ,104], whereas DXA indicates low hip BMD [101]. The lumbar spine BMD may be low but substantially better than the hip BMD [105 ]. MRI typically shows increased water content of the femoral head and marrow, which means that the low DXA value may be an artifact [103,105 , 106,107]. The DXA and MRI findings typically resolve within 2–12 months with 20–40% gains in BMD [97,99 ,100,101,105 ,107,108,109 ]. This condition occurs in men and women of all ages, and so it is uncertain whether its rare appearance during pregnancy is by chance or indicates a pathophysiological connection. It has been theorized to result from such diverse causes as femoral venous stasis due to pressure from the pregnant uterus, Sudeck’s atrophy or reflex sympathetic dystrophy, ischemia, trauma, viral infections, marrow hypertrophy, immobilization, and fetal pressure on the obturator nerve [3,95–97,99 ,104]. It is not a manifestation of altered calciotropic hormone levels or systemic bone resorption during pregnancy. Nevertheless, very low spine BMD, vertebral fractures, severe vitamin D deficiency, and prolonged concurrent pregnancy/lactation cycles have each been reported in a single patient with transient osteoporosis of the hip [82 ,108,110 ,111]. &&

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PATHOPHYSIOLOGY OF OSTEOPOROSIS PRESENTING DURING LACTATION Normal lactation programs’ bone resorption to supply calcium to milk, and that disrupts the microarchitecture of bone and reduces its mechanical strength [3,4]. These changes are most marked and rapid within trabecular bone, which explains why vertebral crush fractures may occur. The decline in BMD during lactation is normally greater in the spine than the hip and clinically silent, but fragility fractures have rarely occurred. These are commonly single fractures although some women have presented with eight to 10 [82 ,112,113 ]. Some fractures may occur because the normal decline in BMD during lactation has not been tolerated, especially if low bone mass, fragility, or secondary causes of bone loss preceded pregnancy. If loss of BMD began during pregnancy, the skeleton will have compromised strength before the normal lactation-induced bone loss occurs. Some fractures may result solely from excessive bone resorption during lactation, such as from overabundant production of PTHrP by mammary tissue. In one documented case of osteoporosis that presented during lactation, plasma PTHrP remained high for months after weaning [114].

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If osteoporosis or very low BMD is present (e.g., a 33-year-old woman with BMD Z-score 4.7 and prior fracture [115]), it may be reasonable to discourage breastfeeding because of the likelihood that BMD will decline further, thereby increasing the risk of fragility fractures.

USE OF PHARMACOLOGICAL OR SURGICAL THERAPY As noted earlier, BMD normally increases during the 6–12 months after weaning, with apparent recovery of prior BMD and strength. In women who developed vertebral compression fractures during pregnancy or lactation, the BMD increased spontaneously by a mean of 10% after weaning (20% in individual cases), suggesting that loss of BMD occurred before the fracture [77,85,116]. The spontaneous BMD increase also means that pharmacological therapy may not be needed, or that its use should be delayed for a year to determine how much recovery occurs naturally [4]. Nasal calcitonin [84,113 ,117], bisphosphonates [76,78 ,80,84,108,112,117–122], strontium ranelate [122], and teriparatide [82 ,84,119,123,124 ] have been anecdotally used in women who fractured during or after pregnancy, but lack of controls leaves uncertainty as to whether the BMD increase exceeded what would have spontaneously occurred [4]. There are safety concerns about long-term use of bisphosphonates [125,126 ,127 ], denosumab [126 –128 ], and strontium ranelate [129 ,130 ] in older women, and so clinicians should carefully consider whether to commit a young woman to long-term treatment without a defined endpoint. Bisphosphonates cross the placenta and theoretically could interfere with fetal endochondral bone development [131,132]; review of 78 cases of use in pregnancy indicated serious adverse effects including fetal mortality [133]. Teriparatide is limited to a lifetime duration of 24 months, and so it may be preferable to reserve it for older ages when the sustained fracture risk is higher. Vertebroplasty [119,134] and kyphoplasty [82 ,113 ,135] have been used to treat painful vertebral fractures postpartum, but the efficacy of this approach is uncertain. Blinded randomized trials have suggested that these procedures are no more effective than sham surgery [136,137]. Furthermore, the presence of cement may increase mechanical strain on adjacent vertebrae, thereby predisposing to more fractures [138–140]. There are no randomized trials or large case series to guide treatment decisions, and so clinical judgment must be used. Pharmacological and surgical treatment should probably be reserved for more severe cases, such as multiple vertebral &

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fractures, persistent disabling pain, or failure to achieve a satisfactory spontaneous increase in BMD after weaning. Patients should be counseled to avoid lifting heavy objects. A supportive corset may be helpful. They should be reassured that vertebral fractures do not usually recur with subsequent pregnancies [94]. Focal, transient osteoporosis of the hip is largely self-limited, with most patients generally requiring only pain relief and continued mobilization. Surgical intervention is needed for hip fractures. It can recur in subsequent pregnancies [106,141], but because it is not a systemic disorder of bone metabolism, there is no clear rationale for pharmacological treatment with antiresorptives or teriparatide.

CONCLUSION Fragility fractures occur rarely during pregnancy, puerperium, and lactation. The cause of these fractures may be multifactorial, including low bone mass or skeletal fragility that precede pregnancy, and the structural and metabolic stresses that may temporarily compromise skeletal strength during pregnancy and especially lactation. Further study is needed to determine when pharmacological or surgical therapy should be used in women who fracture during pregnancy or lactation. Acknowledgements Research grant support from Canadian Institutes of Health Research (grant #133413 and #84253). Conflicts of interest There are no conflicts of interest.

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The symptomatic hip showed typical MRI findings of increased water content in the affected femoral head, and the hip BMD spontaneously increased by 40% during follow-up. 106. Lakhanpal S, Ginsburg WW, Luthra HS, Hunder GG. Transient regional osteoporosis. A study of 56 cases and review of the literature. Ann Intern Med 1987; 106:444–450. 107. Takatori Y, Kokubo T, Ninomiya S, et al. Transient osteoporosis of the hip. Magnetic resonance imaging. Clin Orthop Relat Res 1991; 271:190–194. 108. Aynaci O, Kerimoglu S, Ozturk C, Saracoglu M. Bilateral nontraumatic acetabular and femoral neck fractures due to pregnancy-associated osteoporosis. Arch Orthop Trauma Surg 2008; 128:313–316. 109. Bruscas Izu C, San Juan de la Parra S. Transient osteoporosis of both hips in & pregnancy. Reumatol Clin 2014; 10:58–59. This case shows the classic features of transient osteoporosis of the hip in pregnancy: bilateral symptoms, MRI evidence of edema and effusions, and symptomatic resolution within 2 months after delivery. It demonstrates the recurrent nature of the condition because the left hip had been affected during a pregnancy 6 years earlier. 110. Baki ME, Uygun H, Ari B, Aydin H. Bilateral femoral neck insufficiency & fractures in pregnancy. Eklem Hastalik Cerrahisi 2014; 25:60–62. In this case of transient osteoporosis of the hip, the patient suffered bilateral femoral neck fractures during pregnancy. Low 25-hydroxyvitamin D and a history of prolonged lactation with two simultaneous pregnancies may have contributed to generalized bone loss.

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Postpartum osteoporosis Kovacs 111. Pallavi P, Padma S, Vanitha Anna Selvi D. Transient osteoporosis of hip and lumbar spine in pregnancy. J Obstet Gynaecol India 2012; 62:8–9. 112. Ofluoglu O, Ofluoglu D. A case report: pregnancy-induced severe osteoporosis with eight vertebral fractures. Rheumatol Int 2008; 29:197–201. 113. Ozturk C, Atamaz FC, Akkurt H, Akkoc Y. Pregnancy-associated osteoporo& sis presenting severe vertebral fractures. J Obstet Gynaecol Res 2014; 40:288–292. Two women presented with multiple compression fractures, including five in one patient and 10 in the other. Kyphoplasty was done in one woman, but active treatment was simply of calcium, vitamin D, and nasal calcitonin; consequently, the significant improvement in BMD that occurred in both patients was likely spontaneous. 114. Reid IR, Wattie DJ, Evans MC, Budayr AA. Postpregnancy osteoporosis associated with hypercalcaemia. Clin Endocrinol (Oxf) 1992; 37:298–303. 115. Kovacs CS, El-Hajj Fuleihan G. Calcium and bone disorders during pregnancy and lactation. Endocrinol Metab Clin North Am 2006; 35:21–51. 116. Iwamoto J, Sato Y, Uzawa M, Matsumoto H. Five-year follow-up of a woman with pregnancy and lactation-associated osteoporosis and vertebral fractures. Ther Clin Risk Manag 2012; 8:195–199. 117. Dytfeld J, Horst-Sikorska W. Pregnancy associated osteoporosis–a case report. Ginekol Pol 2012; 83:377–379. 118. Sarikaya S, Ozdolap S, Acikgoz G, Erdem CZ. Pregnancy-associated osteoporosis with vertebral fractures and scoliosis. Joint Bone Spine 2004; 71:84–85. 119. Choe EY, Song JE, Park KH, et al. Effect of teriparatide on pregnancy and lactation-associated osteoporosis with multiple vertebral fractures. J Bone Miner Metab 2012; 30:596–601. 120. Jang JY, Lee JG, Jeong IK, et al. A case of postpregnancy osteoporosis combined with ankylosing spondylitis. Rheumatol Int 2009; 29:1359–1362. 121. Ozcelik B, Ozcelik A, Debre M. Postpartum depression co-occurring with lactation-related osteoporosis. Psychosomatics 2009; 50:155–158. 122. Tanriover MD, Oz SG, Sozen T, et al. Pregnancy- and lactation-associated osteoporosis with severe vertebral deformities: can strontium ranelate be a new alternative for the treatment? Spine J 2009; 9:e20–e24. 123. Hellmeyer L, Boekhoff J, Hadji P. Treatment with teriparatide in a patient with pregnancy-associated osteoporosis. Gynecol Endocrinol 2010; 26:725– 728. 124. Lee SH, Hong MK, Park SW, et al. A case of teriparatide on pregnancy& induced osteoporosis. J Bone Metab 2013; 20:111–114. This 39-year-old lactating woman presented at 3 months postpartum with compression fractures in all five lumbar vertebrae. Teriparatide was prescribed, but no follow-up data are provided. 125. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007; 22:1479–1491. 126. Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and dia&& physeal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2014; 29:1–23. Reviews the data pertaining to atypical fractures of the femur occurring in patients who had received long-term bisphosphonate treatment.

127. Uyanne J, Calhoun CC, Le AD. Antiresorptive drug-related osteonecrosis of && the jaw. Dent Clin North Am 2014; 58:369–384. Reviews the data pertaining to osteonecrosis of the jaw that occurs in association with bisphosphonate and denosumab treatment. 128. Thompson RN, Armstrong CL, Heyburn G. Bilateral atypical femoral fractures && in a patient prescribed denosumab - a case report. Bone 2014; 61:44–47. Atypical fractures have already occurred in patients treated with denosumab despite its relatively short time on the global market. 129. Abrahamsen B, Grove EL, Vestergaard P. Nationwide registry-based analysis && of cardiovascular risk factors and adverse outcomes in patients treated with strontium ranelate. Osteoporos Int 2014; 25:757–762. Increased cardiovascular risk associated with use of strontium ranelate has caused concern and may result in restrictions in whom and for how long it can be prescribed. 130. Donneau AF, Reginster JY. Cardiovascular safety of strontium ranelate: real&& life assessment in clinical practice. Osteoporos Int 2014; 25:397–398. Increased cardiovascular risk associated with use of strontium ranelate has caused concern and may result in restrictions in whom and for how long it can be prescribed. 131. Patlas N, Golomb G, Yaffe P, et al. Transplacental effects of bisphosphonates on fetal skeletal ossification and mineralization in rats. Teratology 1999; 60:68–73. 132. Okazaki A, Matsuzawa T, Takeda M, et al. Intravenous reproductive and developmental toxicity studies of cimadronate (YM175), a novel bisphosphonate, in rats and rabbits. J Toxicol Sci 1995; 20 (Suppl 1):1–13. 133. Stathopoulos IP, Liakou CG, Katsalira A, et al. The use of bisphosphonates in women prior to or during pregnancy and lactation. Hormones (Athens) 2011; 10:280–291. 134. Kim HW, Song JW, Kwon A, Kim IH. Percutaneous vertebroplasty for pregnancy-associated osteoporotic vertebral compression fractures. J Korean Neurosurg Soc 2010; 47:399–402. 135. Bayram S, Ozturk C, Sivrioglu K, et al. Kyphoplasty for pregnancy-associated osteoporotic vertebral fractures. Joint Bone Spine 2006; 73:564–566. 136. Buchbinder R, Osborne RH, Ebeling PR, et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N Engl J Med 2009; 361:557–568. 137. Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med 2009; 361:569–579. 138. Baroud G, Bohner M. Biomechanical impact of vertebroplasty. Postoperative biomechanics of vertebroplasty. Joint Bone Spine 2006; 73:144–150. 139. Baroud G, Nemes J, Heini P, Steffen T. Load shift of the intervertebral disc after a vertebroplasty: a finite-element study. Eur Spine J 2003; 12:421– 426. 140. Han IH, Chin DK, Kuh SU, et al. Magnetic resonance imaging findings of subsequent fractures after vertebroplasty. Neurosurgery 2009; 64:740– 744. 141. Truszczynska A, Walczak P, Rapala K. Transient peripartum osteoporosis of the femoral head in first and third pregnancy. J Clin Densitom 2012; 15:467– 471.

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