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Abstract

Health burden related to osteoporotic fractures in an aging female population far exceeds that imposed by other chronic disorders such as cardiovascular disease and breast cancer. Bone mineral density assessment and clinical risk factors provide independent insights into fracture risk in individuals. A finite list of clinical risk factors are identified as prognostic of fracture risk, namely among aging women, including low body mass, compromised reproductive physiology (e.g., prolonged periods of amenorrhea and early menopause), parental and personal histories of fracture, and alcohol and tobacco use. Pelvic organ prolapse is a common gynecologic entity and a contributor to age-related morbidities. The purpose of this review is to communicate data identifying pelvic organ prolapse as another clinical risk factor for fracture risk in postmenopausal women and to increase the caregiver's vigilance in anticipating and instituting preventive care strategies to a population (i.e., postmenopausal women with clinically appreciable pelvic organ prolapse) that may be at an enhanced lifetime risk for skeletal fractures.

Keywords

aging bone mineral density fracture pelvic organ prolapse postmenopause rectocele

Osteoporotic fractures are significant contributors to morbidity and mortality in an aging population [1,101]; healthcare costs attributed to the management of fragility fractures and related morbidities far exceeds that expended on cardiovascular disease and breast cancer combined. Given the magnitude of morbidity and associated financial burden, the past few decades have witnessed an impetus in efforts aiming to identify individuals with compromised bones who are therefore at risk for fragility fractures [2].

Bone mineral density (BMD) is recognized as a major determinant of skeletal strength. While BMD testing is regarded as the ‘gold standard’ in assessing fracture risk in clinical settings, it is important to appreciate that an individual's risk for fragility fracture may be quantified to a degree comparable with that achieved through BMD testing by paying heed to personal and familial histories [2]. Recognizing that BMD testing may not be universally available nor accessible and appreciating the valuable insight provided by clinical information, the recent years have witnessed efforts to effectively assimilate accessible information (clinical information as well as information regarding BMD if available) for quantifying such risk for an individual, similar to the assessment models for determining individualized risks of breast cancer and CVD respectively [3,4]. Spearheaded by the WHO, fracture risk assessment (FRAX) is a web-based tool that allows for identification of an individual at undue risk for fragility fracture; of note, the tool allows for risk quantification even in the absence of available BMD test results [2,5].

Contributions of the bone connective tissue, predominantly collagen, towards skeletal integrity are increasingly being recognized. While the bone mineral content is recognized to contribute towards stiffness and strength, the collagen component of the matrix offers ductile properties and contributes to postyield properties of the bone and to overall skeletal strength [6,7]. A predisposition to fragility fractures that is recognized with advancing age as independent of changes in BMD is additionally attributed, in part, to changes in the collagen structure and mechanical properties of the bone that has been fractured.

Increased incidence of fractures in individuals with a collagen disorder, for example, Marfan's and Ehlers–Danlos syndromes and osteogenesis imperfecta, underscores the importance of bone matrix collagen in conferring skeletal architectural stability [8 –11]. These latter disorders underscore the importance of ‘bone quality’, an aspect that may be independent of BMD; indeed, the routinely employed BMD assessments utilizing dual x-ray absorptiometery (DXA) are compromised in providing insights into ‘qualitative’ skeletal parameters [12]. BMD is thus just one component conferring strength to the osseous skeleton and may not do justice to qualitative parameters of the bone; indeed, skeletal fragility may exist in the setting of ‘normal’ BMD parameters, as classically noted in patients with Paget's disease [13].

Pelvic organ prolapse (POP) is a recognized contributor to morbidities in an aging female population, and to the overall healthcare cost in the community [14,15]. More than 300,000 surgical procedures are reportedly performed annually for POP in USA alone, with incurred costs in excess of US $1 billion [15]. The prevalence of POP attests to the magnitude of potential healthcare burden attributable to POP; as many as 41% of postmenopausal women enrolled in the Women's Health Initiative Estrogen plus Progestin (WHI-EP) trial demonstrated some degree of POP [14].

While pregnancy, parity, mode of delivery and increased BMI are recognized to predispose an individual to POP, the exact pathophysiological mechanisms remain unclear and are likely multifactorial [16 –18]. A predisposition to POP is suggested in women afflicted by generalized connective tissue disorders including Marfan's and Ehlers–Danlos syndromes [12, 19–21], identifying the importance of a supportive role of pelvic collagen in maintaining architectural tissue topography of pelvic organs. Indeed, both qualitative and quantitative deficiencies in pelvic collagen are suggested in women with POP [22 –29]. Available literature identifies both reduced tissue collagen content as well as a relatively high content of poorly cross-linked immature tissue collagen that is susceptible to degradation, in women with POP; therefore, these mechanisms may independently contribute to the structural compromise of pelvic support and hence predispose to herniation of pelvic organs through a compromised and poorly supportive pelvic floor. Limited data suggest that connective tissue compromised in the setting of POP may not be limited to the pelvis. Indeed, existing data are supportive of a ‘global collagen deficiency’ in the setting of POP [12,30–35]. Hypermobility of joints and altered pulmonary compliance are all described in women with POP and thus support the notion that POP may be a focal manifestation of a generalized connective tissue disturbance.

Given the critical roles for tissue collagen in maintaining tissue specific structural integrity and evidence that women with POP may indeed manifest generalized compromise in their connective tissue, the logical extension of these observations is the pursuit of whether women with POP are at an enhanced risk for skeletal compromise. Of interest is a recognized racial predisposition to POP (more common in the Caucasian population compared with the African race) that is mirrored in a racial predisposition to skeletal fragility (i.e., Caucasians are more likely to suffer from lower BMD and higher skeletal fragility than Africans) [16 –18]. The theory of an underlying compromise of connective tissue may indeed explain the racial bias for the respective disorders and markedly broadens the spectrum of the thus far appreciated morbidities associated with POP ( Table 1 ).

Table 1.

Published literature exploring an association between pelvic organ prolapse and generalized connective tissue disturbance.

Study	Design	Population	Research question	Findings	Comment	Ref.
Stoddard and Myers (1968)	Case report (two cases)	A 33-year-old primigravida with EDS developed POP following spontaneous vaginal delivery. Patient underwent a vaginal hysterectomy at age 35 years with repair of cystocele and rectocele	POP in one of the two discussed cases of EDS identifies generalized connective tissue disturbance to be linked with POP	Postoperative prolapse of vaginal vault and recurrence of enterocele within 1 year of surgery	Relationship between POP and generalized connective tissue disorder is identified in one of the two cases discussed	[12]

Al-Rawi (1982)	Case–control	76 Iraqi women with POP were evaluated for JHM; Control group was age and parity matched women without POP	Joint mobility scores were assigned (0–9); JHM was assessed by modified Carter–Wilkinson criteria	Significantly higher prevalence of JHM in women with POP (66%) compared with controls (18%), p < 0.005	POP was quantified by grade (based on degree of descent relative to the introitus) and by site (anterior or posterior wall prolapse)	[30]
Al-Rawi (1982)	Case–control				Data analyses regarding relationship of joint laxity to grade or anatomical site of POP are lacking	[30]

Marshman et al. (1987)	Case–control	White Australian adults 25 patients (four women and two men) having undergone surgery for complete rectal prolapse (mean age 67 ± SD 20.4 years) and 25 age- and gender-matched general surgical patients without rectal prolapse (controls)	Relationship between joint laxity (5th finger extensibility) and rectal prolapse was assessed	Subjects (either gender) with rectal prolapse demonstrated significantly (p < 0.001) increased joint laxity compared with age- and gender-matched controls	Details regarding concomitant genital prolapse in women with rectal prolapse are lacking	[34]

Norton et al. (1995)	Cross-sectional study, Case–control design	Women attending a multiphysician gynecology clinic in Salt Lake City, UT, USA; 39 with evidence of JHM and 69 controls with normal joint mobility	JHM assessed by modified Carter–Wilkinson criteria 45° and anatomical type of POP (grades 0–3) in those with and without JHM assessed	Women with JHM had a significantly higher prevalence of POP (89%) compared with those with normal joint mobility (58%; p = 0.002). Women with JHM were significantly more likely to exhibit grades 2/3 of cystocele and rectocele compared with those with normal joint mobility	Investigator bias is minimized by blinding of researcher assessing JHM to the status of POP. Association between higher grades of POP and JHM is suggested	[31]

McIntosh et al. (1995)	Case series	Patients with EDS registered on the Ehlers Danlos National Foundation mailing list invited to a multidisciplinary clinic in Detroit, MI, USA. Detailed data on 36 women with EDS are presented.	POP was identified by examination or by history of surgery for prolapse	7/36 (25.9%) of women with EDS (mean age 40.3 ± SD 12.3 years) were identified with POP. No comparative population data for prevalence of POP are provided	No control group, although national norms are provided for some comparisons	[19]
McIntosh et al. (1995)	Case series	EDS was categorized as types I, II and III and prevalence of POP was assessed across the groups				[19]

Mcintosh et al. (1996)	Cross-sectional	Women with EDS registered for the first multidisciplinary EDS clinic sponsored by Ehlers–Danlos National Foundation. Data on POP are available for 38 who underwent orthopedic assessments. Participants classified as incontinent (n = 22) or continent (n = 16) by history	POP was identified by examination (evidence of moderate-to-severe POP is commented upon) or by history of surgery for prolapse.	While women with POP (n = 15) demonstrated higher site-specific JHM at certain joints, the differences were not statistically significant	Expanded EDS population from reference [19].	[20]
			Range of motion and degree of joint mobility of large joints (18 joints assessed using a goniometry). Prevalence of JHM and POP in continent and incontinent women with EDS is compared		No comparative population data for prevalence of POP are provided.
					Note that primary focus of analyses is on relationship of POP and JHM with continence

Bai et al. (2002)	Cross-sectional study, Case–control design	55 women with POP and 62 controls from benign gynecology clinic in Seoul, Korea	JHM reflected by finger extension angle >55°. POP quantified as early (stages I-II) or advanced (III-IV)	Prevalence of JHM was significantly higher in those with POP (42.9 vs 27%; p = 0.002). Proportion of women with JHM was significantly higher in POP-Q stages III and IV than in stages I and II	Higher finger extension angles noted in middle aged (40–59 years) but not in older (>59 years) women with POP versus controls (p < 0.001). A role for altered tissue collagen as an underlying contributor to POP and JHM is suggested. Association between higher grades of POP and JHM is suggested	[32]

Carley and Schaffer (2000)	Cross-sectional	Women with EDS (n = 8) and Marfan syndrome (n = 12) identified through ICD9 diagnostic codes in two urban hospitals in Texas. Information procured through review of medical records and telephone interviews	POP was categorized based on patient's report as POP symptoms only (reported pelvic pressure associated with a protrusion or bulge from the vagina), diagnosed by a physician and reported surgical repair of POP	6/8 (75%) women with EDS (mean age 46 ± SD 20 years) and 4/12 (33%) with Marfan syndrome (mean age 49 ± 12 years) reported features of POP	No comparative population data for prevalence of POP are available. Authors suggest a role for differences in tissue collagen and fibrillin as contributors to higher prevalence of POP in this patient population	[9]

Strinic et al. (2002)	Case–control	40 premenopausal patients admitted to hospital for surgical correction of genital prolapse and 40 matched female examinees without prolapse	Pulmonary ventilatory function was examined	Patients with prolapse exhibited significantly decreased expiratory flows, especially in the peak expiratory flow (−26%) and other flows at large lung volumes. The forced vital capacity and forced expired volume at 1 s were also decreased (−9 and −16%, respectively)	A link between collagen deficiency and impairments of pulmonary function in women with POP is suggested as a reflection of global collagen defects in women with POP	[33]

Table 2.

Published literature exploring an association between pelvic organ prolapse and skeletal fragility.

Study	Design	Population	Research question	Findings	Comment	Ref.
MacLennan et al. (2000)	Cross-sectional; The South Australian Health Omnibus Survey	Community dwellers (either gender) were surveyed for symptoms of pelvic floor dysfunction	Participants were asked regarding symptoms of pelvic floor dysfunction and of POP. Determinants of pelvic floor dysfunction and POP were sought; history of osteoporosis was included in the list of questions participants were asked to respond to	Significant relationship was observed between symptoms of POP or of pelvic floor dysfunction and known diagnosis of osteoporosis	Verbal reporting of history of osteoporosis may not reflect the exact magnitude of this disease in the population surveyed.	[35]
MacLennan et al. (2000)	Cross-sectional; The South Australian Health Omnibus Survey				No objective determination of POP is available and, hence, the relationship between osteoporosis and worsening grades of POP cannot be commented upon	[35]
Melton et al. (2007)	Case–control; Olmstead County cohort	9258 women undergoing hysterectomy in the period 1965–2002 and subsequently followed for a median period of 13.6 years	Incident skeletal fractures and their relationship to indication of hysterectomy was explored	Enhanced risk for osteoporotic fractures was identified in women who underwent hysterectomy for an indication of uterine prolapse (HR: 1.33; 95% CI: 1.01–1.74) compared with age- and sex-matched community controls	No details are available on grade of nor on the anatomical variants of POP	[37]
Pal et al. (2008)	Nested case–control design within a RCT	Baseline data in postmenopausal women approximately 60 years age enrolled in the WHI-EP arm. POP was quantified as moderate-to-severe versus absent-to-minimal	Self-reported fractures sustained in older age (>55 years age) were identified as outcome of interest.	Association between moderate-to-severe POP and significantly increased likelihood for ever fractures (adjusted OR: 1.24; 95% CI: 1.03–1.51; p = 0.03).	Relationship between moderate-to-severe POP and history of fracture was most robust for moderate-to-severe rectocele	[42]
Pal et al. (2008)	Nested case–control design within a RCT		BMD testing was available in a subset of participants	A higher prevalence of low BMD in women with moderate-to-severe POP compared with those with absent-to-minimal POP	Relationship between moderate-to-severe POP, especially rectocele and history of fracture was independent of age, race, BMI, family history of fracture, smoking, age at menopause, parity, socioeconomic status, history of falls or of thyroid disease or emphysema (adjustment variables were identified as relating to fracture history on univariate analyses)	[42]
Pal et al. (2008)	Retrospective cohort analysis of a RCT	Longitudinal data in postmenopausal women enrolled in the WHI-EP arm	Incident fractures (overall) and site-specific fractures and relationship with mild-to-moderate versus absent-to-mild POP	Increased risk for hip fracture in women with moderate-to-severe compared with those with minimal-to-absent POP	Relationship between moderate-to-severe POP and incident hip fracture was most robust for moderate-to-severe rectocele (adjusted HR: 2.15; 95% CI: 1.13–4.11; p = 0.020).	[43]
Pal et al. (2008)	Retrospective cohort analysis of a RCT				Relationship between moderate-to-severe POP, especially rectocele and incident hip fracture was observed to be independent of age, BMI, race, family history of fracture, regular menses, age at menopause, nulliparity, hormone use, history of falls, income, calcium supplementation, METs per week, asthma, emphysema, thyroid and hormone-replacement therapy arm	[43]

HR: Hazards ratio; MET: Metabolic equivalent; OR: Odds ratio; POP: Pelvic organ prolapse; RCT: Randomized, controlled trial; WHI-EP: Women's Health Initiative Estrogen plus Progestin.

A review of English-language literature was conducted utilizing the PubMed search engine and using search terms, ‘pelvic organ prolapse’, ‘genital prolapse’, ‘rectocele’, ‘cystocele’, ‘uterine prolapse’, ‘collagen’, ‘connective tissue disorder’, ‘fracture’, ‘fragility fracture’, ‘osteoporosi’ and ‘low bone density’. Bibliographies of the identified publications were hand searched for any additional relevant articles. Also included is an abstract (details follow) that was not identified through the PubMed search.

Table 1 identifies the published studies that suggest that POP may be associated with generalized connective tissue compromise. In 1987, Marshman et al. demonstrated joint hypermobility in patients with rectal prolapse [34]; this small study, beyond supporting the concept of a global connective tissue deficiency in patients with rectal prolapse, added to the phenotypic spectrum of POP [35].

Existing data that suggest a relationship between POP and skeletal fragility are identified in Table 2 . MacLennan et al., in a cross-sectional population study of the prevalence of pelvic floor dysfunction in the community (The South Australian Health Omnibus Survey) was the first group to describe a relationship between disordered pelvic floor function and osteoporosis [36]. A total of 3010 community dwellers aged 15–97 years were randomly selected, of which 51.3% were women (mean age 44.8 ± SD 19.04 years) who were interviewed for symptoms of pelvic floor dysfunction; the participants were asked about medically confirmed comorbidities, including osteoporosis. A significant relationship was observed between known osteoporosis and symptoms consistent with pelvic floor dysfunction or problems (stress or urge incontinence, flatus or fecal incontinence, current symptoms of vaginal prolapse or prior surgery for prolapse); the relationship remained statistically significant on analyses adjusting for multiple parameters identified to be of relevance in the context of pelvic floor dysfunction (HR: 1.80; 95% CI: 1.0–3.2; p = 0.049). In the context of their observations regarding pelvic floor dysfunction and relationship with parity and route of delivery, the authors comment in detail on modulations in the pelvic connective tissue in pregnancy and thereby rationalize mechanisms that may underlie connective tissue compromise therein. From the perspective of this review, the authors conjectured that hereditary connective tissue disorders might explain the observed relationships between pelvic floor dysfunction and osteoporosis; this is the first suggestion that connective tissue deficiency may indeed be a common pathophysiological mechanism that could explain the observed relationships between pelvic and skeletal compromise. Of interest is a single case report from the veterinary literature that identifies coexistent rectal prolapse and pelvic fracture in a free-ranging African black rhinocerous [37]; this observation builds upon the earlier reported suggestions of generalized connective tissue disturbance in the context of rectal prolapse put forth by Marshman et al. [35].

The theoretical plausibility of a relationship between POP and skeletal fragility is further strengthened by a recently published work by Melton et al. [38]; in a large retrospective cohort study of 9258 women undergoing hysterectomy between the period 1965 and 2002 and subsequently followed (median follow-up period of 13.6 years) for skeletal fractures, the authors identified an enhanced risk for osteoporotic fractures in women who underwent hysterectomy for uterine prolapse (HR: 1.33; 95% CI: 1.01–1.74) compared with age- and sex-matched community controls. While limitations intrinsic to the study design did not allow for exploration of mechanisms that may underlie the observed relationships, the authors proposed that underlying estrogen deficiency may be a unifying pathophysiological mechanism that may explain the observed relationship between uterine prolapse as an indication for hysterectomy and subsequent fractures. In this latter regard, while implications of hypoestrogenemia in the causation of skeletal compromise and fragility are well recognized, a role for the lack of estrogen in the causation of POP is far from substantiated [39 –42].

The WHI-EP trial provided a unique opportunity to explore the relationship between POP and skeletal fragility [43], given that evaluation for POP constituted an integral component of the physical examination in the enrolled population [14]. Skeletal fragility was reflected in participants acknowledging ‘ever breaking a bone’ and ‘breaking a bone after 55 years of age at baseline; analyses were restricted to postmenopausal women 60 years or older (n = 11,086). Overall, 19% of the population acknowledged sustaining a fracture after 55 years of age. Pursuing a hypothesis that if indeed POP is a focal manifestation of a generalized collagen disturbance, postmenopausal women with evidence of POP may be at an enhanced lifetime risk for skeletal fragility, an association between moderate-to-severe POP (any anatomical variant) and significantly increased likelihood for fractures (adjusted odds ratio [OR]: 1.24; 95% CI: 1.03–1.51; p = 0.03) was observed. Of further interest was a site-specific heterogeneity in the anatomical variants of POP (i.e., cystocele, rectocele and uterine POP) in their relationship with fracture history; the most robust associations between skeletal compromise and POP were observed in women with moderate-to-severe rectocele (adjusted OR: 1.45; 95% CI: 1.07–1.95; p = 0.01). In the subset of women undergoing BMD testing in the WHI-EP trial, prevalence of low BMD (defined as BMD > 1 standard deviation below the mean for the population at any measured skeletal site) was almost twice as higher in women with moderate-to-severe POP compared with those with absent or minimal POP (unadjusted OR: 2.16; 95% CI: 1.34–3.50; p < 0.001). Significantly lower BMD (gm/cm²) was evident at the femoral trochanter (0.92 ± 0.13 vs 0.97 ± 0.16; p = 0.03) and whole body (0.94 ± 0.09 vs 0.97 ± 0.09) in women with moderate-to-severe POP compared with absent or minimal POP. Multivariable regression analyses identified moderate-to-severe POP as an independent predictor of whole body BMD after adjusting for age, BMI, age at menarche, menstrual history, early menopause (defined as menopause at age < 45 years), personal or family history of fracture, smoking history, measures of physical activity and socioeconomic status. While the observed decreased BMD parameters in women with moderate-to-severe POP may indeed be a reflection of compromised tissue collagen (skeletal collagen provides the infrastructure of the bone matrix for subsequent mineralization), given the retrospective nature of the analyses, this latter conjecture at present remains unsubstantiated.

Furthering the initial observations noted in baseline data from the WHI-EP trial, analyses of the longitudinal data for the WHI-EP trial [44] demonstrate that postmenopausal women with moderate-to-severe POP are significantly more likely to experience incident hip fractures compared with those with absent or minimal POP. In keeping with earlier observations, the association with incident hip fracture was most robust for moderate-to-severe rectocele [Presented at: The 19th Annual Meeting of the North American Menopause Society, Orlando, FL, USA 24–27 September 2008; Unpublished Datal.

While this review has been an attempt to assemble published data that have explored relationships between POP and skeletal fragility (as reflected by either decreased BMD or fracture risk), the significant limitations of the existing data cannot be ignored. Case reports, case–control studies and subpowered cross-sectional analyses are fraught with potentials for all kinds of biases; any associations described may well be reflective of a major error (i.e., spurious statistical significance in the absence of any real association). The biological plausibility of the proposed relationships between pelvic connective tissue and skeletal integrity and the consistency of observations on analyses of the single randomized, controlled trial [43,44] however add credence to the hypothesis that POP may indeed help identify postmenopausal women at an enhanced fracture risk.

Conclusion

Although sparse, existing data do identify POP as a focal manifestation of a generalized connective tissue compromise and identify a relationship with skeletal compromise in postmenopausal women with POP; a dose–response phenomenon to this relationship with worsening degree of POP is further suggested. As the medical community strives to identify individuals at risk for future fracture to allow for timely institution of preventive care strategies, existing data identify that postmenopausal POP may indeed ‘flag’ a compromised skeleton; the spectrum of health morbidities that may be impacted upon by critical contributions of gynecologists thus stands further enhanced by data discussed in this review. Detection of pelvic decensus should therefore prompt initiation of a detailed enquiry into individualized fracture risk assessment in a population (i.e., postmenopausal women with POP) that, based on this review, should be deemed at risk for skeletal fracture. Given the prevalence of POP (41% of postmenopausal women enrolled in the WHI-EP trial were identified with POP [14], and almost 8% demonstrated moderate-to-severe grades of prolapse [43]), and the observed associations of moderate-to-severe POP (any anatomical variant) and moderate-to-severe rectocele in particular with the most morbid of fractures (that of hip), targeted management aimed at optimizing osseous health in a population deemed at an enhanced fracture risk may indeed hold implications for public health.

Future perspective

Site-specific differences in tissue collagen and relationships therein with skeletal integrity are suggested by analyses of the WHI-EP trial data; while these findings may reflect inherent differences in the collagen within the pelvic fascial compartments, an alternative explanation may be that rectocele identifies a greater magnitude of connective tissue compromise compared with other anatomical variants of POP (i.e., cystocele or isolated uterine prolapse) [43]. However, these latter assumptions remain unsubstantiated and merit further exploration of site-specific differences in pelvic fascia and their relationship with skeletal collagen in future studies.

Executive summary

Pelvic organ prolapse (POP) is a common gynecological entity that may affect more than a third of the postmenopausal population.

Morbidities of POP may not be limited to isolated gynecological symptoms.

Fragility fractures are significant contributors to health morbidities in an aging population.

Future studies are needed to further understand mechanisms that unify POP with fracture risk.

Caregivers must appreciate that postmenopausal women with clinically appreciable POP may be at an enhanced risk for skeletal fracture and hence represent a population that is likely to benefit from targeted preventive care strategies (i.e., fracture risk assessment utilizing available tools, lifestyle modifications, improved musculoskeletal coordination and individualized management) in order to minimize fracture risk.

Footnotes

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Pelvic Organ Prolapse and Relationship with Skeletal Integrity

Abstract

Keywords

Conclusion

Future perspective

Footnotes

References