Osteogenesis Imperfecta

C H A P T E R

55 Osteogenesis Imperfecta: Maintenance of Adult Bone Health Jay R. Shapiro and Feng-Shu Brennen Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD, USA

INTRODUCTION Experience dictates that (1) the medical literature contains relatively few references to the treatment of adults with osteogenesis imperfect (OI) and (2) the primary care physician has, at best, limited or no experience in treating adults with OI. As a result, when medical problems occur in the OI individual they may be approached apart, or out of context, from a patient’s systemic connective tissue disorder. Other chapters in this text cover certain disorders found in adults with aging, dental care (Chapter 33), osteoarthritis (Chapter 38) and hearing (Chapter 32). This chapter will focus on the maintenance of bone health in adults with OI. The role of vitamin D and the maintenance of normal vitamin D levels and calcium metabolism are discussed in Chapter 56 but are included here as vitamin D and calcium metabolism impact bone health in adults with OI. However, when discussing bone health in adults with OI, it is important to note that there is little information that accurately describes the changes in bone mineral density or in fracture rate.

BONE METABOLISM IN ADULT AGING AND IN ADULTS WITH OI The skeleton is subject to deleterious effects from aging which can predispose an individual to osteoporosis and related fractures. This burden of aging is superimposed upon the diminished bone mass in adults with OI and is potentially complicated by the presence of skeletal deformities which alter bone structure and weaken bone strength. In children, bone turnover is generally increased in moderate to severe Osteogenesis Imperfecta. DOI: http://dx.doi.org/10.1016/B978-0-12-397165-4.00055-1

OI phenotypes: bone formation and resorption may remain coupled. However, in the adult, aging decreases osteoblastic bone formation and increases osteoclastic bone resorption thus accentuating late onset bone loss and increasing the fracture risk as the individual ages. Although increasing information is available as to the significant role of osteocytes in regulating bone metabolism, this has not been investigated in OI.1 However, we lack detailed information as to the mechanisms whereby cellular aging alters skeletal homeostasis under normal circumstances and limited information which specifically addresses the effect of aging in OI on bone cell metabolism. Aging effects specifically related to OI may encompass the following: age-related changes in type I collagen, age-related effects on osteoblast, osteoclast or osteocyte function, and changes in matrix composition affecting proteoglycan synthesis (see Chapter 8). Bone mass and bone strength decline with age. As categorized by Manologas,2 small bone size, disrupted bone architecture, the potential for delayed repair of fatigue microdamage and suppressed bone turnover in adults with OI are additional factors that increase age-related susceptibility to fracture. The agerelated decline in cortical bone tensile strength may be caused by deterioration of type I collagen, resulting from lost crosslinking between the component chains3 and accumulation of advanced glycation end products4 – another general feature of the aging process which has not been assessed in bone from OI individuals.2 Studying osteoblast gap junctions, Genetos et  al. observed no effect of age per se upon osteoblastic Cx43 mRNA, protein or gap junctional intercellular communication (GJIC). However, the authors have demonstrated an age-related impairment in the capacity of

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55.  Osteogenesis Imperfecta: Maintenance of Adult Bone Health

Fibroblasts

Osteoblasts (B)

1.6

2.8

1.2

2.1

0.8

1.4 NL neonatal

NL 5y

NL 24y

NL 11y

NL 44y

NL 41y

Ln(N/N0)

0.4 0.0

0.7

0.0 (C)

(D)

OI I 8y

1.6

OI III 13y

Ln(N/N0)

(A)

2.8

OI I 24y 1.2

2.1

0.8

1.4 OI I 14y OI III 22y

0.4

0.7

OI I 58y 0.0

0

3

6

9

12 0 6 Days in culture

12

8

24

0.0

FIGURE 55.1  Growth rates in representative normal and OI fibroblasts and osteoblasts.6 Human fibroblasts (A and C) and osteoblasts (B and D) derived from normal and OI patients were followed for up to 2 weeks of culture. Normal and OI osteoblasts were followed for up to 4 weeks of culture. In contrast to fibroblasts, osteoblast growth rates are significantly impaired.

osteoblastic cells to generate functional gap junctions in response to parathyroid hormone (PTH) and suggest that an age-related defect in G protein-coupled adenylate cyclase activity at least partially contributes to decreased PTH-stimulated GJIC.5 If occurring in older patients with OI, this could contribute to the failure of teriparatide to decrease fracture rate in adults with OI, as discussed below. Fedarko et  al. have investigated the growth characteristics of dermal fibroblasts and trabecular osteoblasts isolated from patients with OI type I and III, and from control subjects of different ages (Figure 55.1).6 Both age and OI type dependence are illustrated in osteoblast growth patterns. Three parameters, which are markers for biologically relevant growth parameters, were measured: the plateau value or upper asymptote, which reflects the maximum cell density upon confluence; the maximal growth rate (microM) and the lag time. Both normal human fibroblasts and osteoblasts showed an age-dependent decrease in maximal growth rate. Normal fibroblasts exhibited no age dependence to their upper asymptote or lag time. In contrast to osteoblasts, fibroblasts derived from patients with OI did

not have significantly different upper asymptote values of microM or lag times when compared with normal fibroblasts. In OI, various degrees of bone mineralization are observed at the tissue level: hypermineralization and areas of decreased mineralization are a feature of bones in certain patients with OI.7 This has recently been associated with specific mutations in CRTAP (cartilage associated protein).8 Osteocytes may play a role in regulating mineralization and osteocyte viability may be important in this function. While the basis for loss of osteocyte viability and cell death with age is not fully understood, osteocyte apoptosis, by altering perilacunar mineralization, may contribute to matrix hypermineralization and may potentiate microdamage.9

BIOMARKERS OF BONE TURNOVER The proteins collectively termed “bone biomarkers” reflect the bone forming activities of osteoblasts and the bone resorbing activity of osteoclasts. Clinically, they are used to assess the bone turnover rates and are helpful

XI.  PHARMACOLOGIC TREATMENT OF OSTEOGENESIS IMPERFECTA

Biomarkers of Bone Turnover

TABLE 55.1  Bone Biomarkers Markers of Bone Formation

Source

Osteocalcin

Osteoblast

Type I collagen N-propeptide (PINP)

Cleaved following collagen processing

Bone-specific alkaline phosphatase (AP)

Osteoblast

Type I collagen C-propeptide (PICP)

Cleaved following collagen processing

Total alkaline phosphatase

Osteoblast

Markers of Bone Resorption

Source

N-terminal telopeptide (NTX)

Cleaved following collagen processing

C-terminal telopeptide (CTX)

Collagen crosslinks

Pyridinoline (PYD)

Collagen degradation products

Hydroxyproline (HYP)

Collagen degradation products

Deoxypyridinoline (DPD or D-Pyr)

Collagen degradation products

Tartrate-resistant acid phosphatase (TRAP5b) Osteoclast

in determining the response to various treatments. The commonly used bone biomarkers are listed in Table 55.1. Rauchenzauner et  al. provided sex- and age-specific reference curves for serum bone formation (osteocalcin and bone alkaline phosphatase) and bone resorption markers (ICTP, CTX and TRAP 5b) in children aged 2 months to 18 years.10 In general, and consistent with higher rates of bone turnover, higher serum concentrations of bone markers are observed in infancy and mid-puberty.11–16 Astrom et al. have pointed out that in children, measurement of biomarkers is more complex because both bone modeling and remodeling occur, which are influenced by gender, Tanner stage, wholebody bone mineral content, height velocity and the rate of whole-body bone mineral content.17 Of interest was the observation that there were no significant differences between OI types I, III and IV and a nonambulatory, immobilized comparison group according to age, gender, serum PTH or urinary deoxypyridinoline (DPD)/creatinine.

Bone Biomarkers Reflecting Bone Formation in Adults with OI In adults with OI, high, normal or low concentrations of bone biomarkers have been reported. Serum total alkaline phosphatase (AP), bone-specific AP and osteocalcin were reportedly 50 to 200% higher in OI adults than in controls.18 Osteocalcin levels were also reported to be high in OI adults.19 However, Cepollaro

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et  al. reported that serum levels of total AP and osteocalcin were slightly higher in OI adults than in controls but the differences were not significant. Reports have indicated that serum procollagen I-N-terminal propeptide (PINP) was lower than in controls, suggesting a lower rate of type I collagen synthesis.19–21 However, Lund et  al. reported both osteocalcin and PINP were normal in OI adults.22 Shapiro reported that osteocalcin values were low in 40% of OI adults.23 Additionally, low plasma concentration of PICP (type I collagen C-propeptide) has been reported in OI patients suggesting diminished osteoblast activity in the presence of type I collagen mutations.20,22–26 Adults with OI type I had lower PICP levels than did adults with OI III and IV.22 However, no relationship of biomarker levels to specific type I collagen mutations has been reported.

Bone Biomarkers Reflecting Bone Resorption Biomarkers of bone resorption may be specifically helpful in following the response to different treatment modalities including the response to anti-resorptive treatment. Shapiro reported low excretion of deoxypyridinoline (DPD) in 40% of OI adults and high excretion in 20%.23 Braga et  al. reported that urinary DPD and N-terminal crosslink telopeptide (NTX) were higher in adults with OI than in controls: patients with OI type III and IV had significantly higher values than patients with type I OI. However, serum C-terminal telopeptide (CTX) levels were normal.18,22 In OI adults, Lund reported that CTX levels were higher in OI type III and IV than in OI type I.22 Cepollaro et al. reported that urinary excretion of hydroxyproline (HYP) and pyridinoline (PYD) were slightly, but not significantly, higher in OI adults.20 Garero et al. first reported increased levels of type I collagen helical peptide and a higher ratio of the native (αCTX) isoform to isomerized C-telopeptide (βCTX) in OI adults.19 Wekre et  al. reported that the bone marker levels in OI adults didn’t show a major difference from normal. However, consistent with other reports, adults with OI type III had higher bone resorption marker levels than adults with OI type I or IV.27 Garnero et  al. have suggested that non-enzymatic post-translational modifications of collagen, urinary type I collagen helical peptides and the ratio of the native (αCTX) to isomerized C-telopeptide (βCTX) may be more reliable indices of overall bone resorption and bone matrix maturation in patients with OI.19

Bone Biomarkers as Reflecting Treatment Results and Compliance Bisphosphonates are currently the most commonly prescribed bone active agents for individuals with OI. Bisphosphonates vary widely in potency but share the

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effect of inhibiting the mevalonate pathway and protein prenylation in the osteoclast, thus decreasing bone resorption.28 Shortly after starting treatment serum CTX will decrease followed by a decline in osteocalcin and alkaline phosphatase. The extent of these changes will vary with the individual bisphosphonate, being more profound with the newer nitrogen-containing bisphosphonates (see Chapter 53). Although several studies have suggested that bone biomarkers may help predict the fracture risk in the osteoporotic elderly,29–31 no consensus on the relationship of bone biomarkers and fracture rate has been reached in adult OI patients. In summary, conflicting data for the effects of treatment on bone biomarkers may be due to (1) the patient’s ambulatory status may alter biomarker levels, and (2) environmental factors (medications, hormonal status, physical activities, etc.) could confound interpretation of the bone biomarker levels.23

to bisphosphonate treatment.33 A total of 210 patients were studied. A favorable response to bisphosphonate therapy was seen in 47% (N = 99/210). As noted above by Peris, patients with a mean 25(OH)D ≥33 ng/ml had ~4.5-fold greater odds of a favorable response (P <0.0001). Confirming the relationship between serum 25(OH)D levels and the response to bisphosphonate, a 1 ng/ml decrease in 25(OH)D was associated with an ~5% decrease in odds of responding. Although the applicability of these results to the generally negative bisphosphonate treatment response in adults with OI is not clear, it would appear that adults with OI should maintain normal serum 25(OH)D levels in order to maintain adequate calcium and phosphorus absorption and adequate bone mineralization. However, excessive intake with vitamin D (or calcium) is not warranted in order to avoid increasing urinary calcium excretion and a potential increase in renal stone formation.

VITAMIN D AND THE RESPONSE TO TREATMENT IN ADULTS WITH OI

DIETARY CALCIUM SUPPLEMENTS IN ADULTS WITH OI

Vitamin D metabolism in OI is discussed in Chapter 56. As is common to other adult populations, vitamin D insufficiency occurs in approximately 50% of OI adults. In postmenopausal osteoporosis, serum 25-hydroxyvitamin D [25(OH)D] levels are associated with the response to bisphosphonate treatment.33 However, the relationship of vitamin D sufficiency to pharmacological treatment in adults with OI has not been addressed. Peris et al. assessed the role of vitamin D in determining the response to standard bisphosphonate treatment for 120 postmenopausal osteoporotic women (aged 68 ± 8 years) receiving alendronate or risedronate.32 This study analyzed the change in bone mineral density (BMD) serum PTH, 25(OH)D and urinary NTx levels. Inadequate response to antiosteoporotic treatment was based on a BMD loss >2% and/or the presence of fragility fractures during the preceding year. Thirty percent of patients showed inadequate response to blood pressure treatment, with significantly lower levels of 25(OH)D (22.4 ± 1.3 vs. 26.6 ± 0.3 ng/ml), a higher frequency of 25(OH)D levels <30 ng/ml (91% vs. 69%) and higher urinary NTx values. The probability of an inadequate response to bisphosphonate was four-fold higher in patients with 25(OH)D <30 (OR, 4.42; 95% CI, 1.22–15.97, p = 0.02). Patients with 25(OH)D >30 ng/ml had a greater significant increase in lumbar BMD than women with values <30 ng/ml (3.6% vs. 0.8%). In a similar manner, Carmel et al. found that in postmenopausal osteoporosis patients, serum 25(OH)D level was strongly associated with a positive response

Total daily calcium intake by adults with OI is highly variable. Standards for calcium supplementation in all adults have been recommended by the Institute of Medicine Committee convened to Review Dietary Reference Intakes for Vitamin D and Calcium.34 Recommended values proposed for healthy individuals were as estimated average requirements (EARs) and recommended dietary allowances (RDAs) or, alternatively, adequate intakes (AIs). The recommendations for adults 19 through 50 years of age were: EAR 800 mg/day and RDA 1000 mg/day. For men 51 through 70 years of age: EAR 800 mg/day calcium; for women 51 through 70 years of age: EAR 1000 mg/day calcium, RDA 1200 mg/day calcium. And for adults >70 years of age: EAR 1000 mg/day calcium, RDA 1200 mg/day calcium. Such standards for adults with OI have not been determined. Important considerations for this would include total diet intake in addition to supplements, the influence of body size on calcium requirements and the potential negative effect which includes hypercalcuria or renal stone formation.

BISPHOSPHONATE TREATMENT IN ADULTS WITH OI The results of bisphosphonate treatment in children have in general been positive: decreasing musculoskeletal pain, permitting vertebral growth and decreasing fracture risk by approximately 50%.35 However, several exceptions exist: intravenous bisphosphonates such as

XI.  PHARMACOLOGIC TREATMENT OF OSTEOGENESIS IMPERFECTA

Bisphosphonate Treatment in Adults with OI

pamidronate appear more effective than orally administered bisphosphonate (alendronate, residronate) in decreasing fracture incidence.36,37 While many children do respond, there is a sizable population of children who do not decrease their fracture risk during bisphosphonate treatment. Children treated with pamidronate may also experience limb fractures even when the limb is rodded. The generally favorable outcomes in children have proven more difficult to demonstrate in adults for several reasons. First, the measurement of BMD by dual X-ray absorptiometry (DXA) is more difficult in many OI adults because of the progression of their bone deformity over time. OI adults frequently have surgical hardware in their limbs or spine which affects the ability of these sites to be measured by DXA. Second, unlike the relatively high fracture rate in children, the incidence of fractures decreases dramatically after puberty. Thus, assessing fracture incidence in response to treatment during mid-life is more difficult. Finally, treatment results are harder to assemble in adults because compliance with both testing schedules and treatment is less stringent for adults as compared with children whose parents oversee the details involved in day-to-day care.38 Considering the widespread use of bisphosphonates in osteoporosis treatment, it was recognized that they would be administered to adults with OI. This has involved both oral and intravenous medications; the results of these trials are summarized below. To date, these clinical studies are compromised by the relatively small numbers of each reported OI type. In interpreting the results of treatment studies, it is important to note that OI is not equivalent to postmenopausal osteoporosis so that treatment results are not comparable to those in the osteoporotic population. Chevrel et  al. studied the effects of oral alendronate on BMD in 64 adult patients in a 3-year randomized placebo-controlled trial.39 Patient distribution was Sillence OI type: type I/type IV; 33/0 and 29/2 for placebo and treatment groups, respectively. Each patient received 1000 mg elemental calcium and 800 IU of vitamin D3 daily. Mean increases in the lumbar spine BMD were 10.1 ± 9.8%, total hip BMD increased by 3.3 ± 0.5%. Although the sample size was not sufficient to determine an effect of alendronate on fracture rate the incidence of vertebral and peripheral fractures was not significantly different between the alendronate and placebo groups. Two vertebral and 17 peripheral fractures occurred in eleven patients in the placebo group versus no vertebral and 17 peripheral fractures in ten patients in the alendronate group. Adami et  al. treated 46 OI adults for 2 years at 3 month intervals with intravenous neridronate compared with a no-treatment group of 23 individuals.40

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The patients were randomized according to OI type (type I or type III and IV) to either i.v. neridronate or no treatment. Spine and hip BMD rose by 3.0 ± 4.6% (SD) and by 4.3 ± 3.9%, respectively, within the first 12 months of treatment, and an additional 3.91 and 1.49% during the second year. One vertebral fracture and one limb fracture occurred in the control group during the first year of observation. One limb fracture was recorded in the treatment patients, but no fractures occurred in the control group while on treatment during the second year of follow-up. Overall, 18 clinical fractures during 4 years prior to recruitment had been reported by 16 patients. The difference in fracture incidence during treatment and during pooled prerecruitment and control times was “at the limit of significance” (p = 0.03; Fisher’s exact t-test). The authors concluded that a trend for a reduction in fracture rate was observed, which was significant by pooling retrospective and prospective events. Although the study was not powered for such an endpoint the results may be considered inconclusive. Pavon de Paz et  al. carried out a prospective nonrandomized study in ten OI patients with “osteoporosis or severe osteopenia (T score<−2)” who could not use oral bisphosphonates.41 Zoledronic acid was administered i.v. every 6 months. Treatment increased BMD measured in the lumbar spine after 24 and 36 months. Significant increases in BMD were also observed after 24 months in the femoral neck. Serum Ca, P, bone alkaline phosphatase and CTX concentrations remained unchanged, which is not expected as bone biomarkers will decrease with zoledronic acid infusions. However, effect on fracture rate could not be evaluated as none of the patients had new fractures. Shapiro et  al. analyzed the results of treatment with oral and intravenously administered bisphosphonates in 90 adults with OI with the following distribution of OI types: 63 type I, 15 type III and 12 type IV. The age range was 17–68 years, mean (SD) age was 39 (11) years. Males and females were grouped for this analysis. Adults were treated with intravenous pamidronate (n = 28), oral alendronate (n = 10), residronate (n = 17) or not treated (n = 35). BMD results were observed for up to 161 months, following an average of 52 months of treatment (Figure 55.2A and B). This study demonstrated that intravenous pamidronate and the oral bisphosphonates, alendronate and residronate, both have a positive effect on BMD when measured as the annualized linear rate of change in BMD after a minimum of 13 months of treatment. In type I patients, BMD was increased by both pamidronate and the oral bisphosphonates at L1–L4 and by the oral bisphosphonates at the total hip. In type III/IV patients pamidronate increased BMD at the L1–L4 site and at the total hip. The oral agents did not increase

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55.  Osteogenesis Imperfecta: Maintenance of Adult Bone Health

(A)

L1L4

Hip

.1

Change in BMD(gm/cm2)

.05 0 –.05 1

2

3

4

5

Femoral neck .1 Treatment group

.05

No treatment

0

Pamidronate Alendronate/residronate

–.05 1

2

3

4 5 Years from baseline BMD

(B) L1L4

Hip

.1 .05

Change in BMD(gm/cm2)

0 –.05 1

2

3

4

5

Femoral neck .1 Treatment group

.05

No treatment Pamidronate

0

Alendronate/residronate

–.05 1

2

3

4 5 Years from baseline BMD

FIGURE 55.2  (A) Projected levels of BMD change for type I OI patients by treatment group and site starting at a baseline measurement across a span of 5 years. The projected BMD changes are based on annualized linear rates of change (95% CI) adjusted for age at baseline DXA scan and gender. (B) Projected levels of BMD change for type III/IV OI patients by treatment group and site starting at a baseline measurement across a span of 5 years. The projected BMD changes are based on annualized linear rates of change (95% CI) adjusted for age at baseline DXA scan and gender.

BMD at the hip in the type III/IV patients. Analysis of the site-specific effects of bisphosphonates on BMD indicated that the femur neck was unresponsive to bisphosphonate treatment. While the reason for this disparity was not apparent, experience in patients with age-related osteoporosis indicates that the BMD response to bisphosphonates at the femur neck is frequently less than that observed at the lumbar spine.42 Pamidronate led to a significant decrease in fracture

rate only in the type III/IV patients during the 5-year period of observation (p =  0.05): fracture incidence did not decrease in the type I patients. First, the postto pre-treatment fracture ratio decreased, but not to a significant extent in all groups including the nontreatment group, except for type I patients with pamidronate or oral bisphosphonate treatment where the ratio increased to a marginal extent. We suggest that this improvement in the non-treatment group illustrates

XI.  PHARMACOLOGIC TREATMENT OF OSTEOGENESIS IMPERFECTA

Agents Under Study with Potential Application to OI (Circa December 2012)

the influence that inclusion in a structured clinical program may have in determining treatment outcomes. For example, inclusion in the study could have resulted in improved vitamin D and calcium intake or alterations in activity could have lessened fracture risk. The marginal increase (p = 0.06) in the post- to pre-treatment ratio of fractures for pamidronate-treated patients compared to non-treated patients requires a larger number of observations to confirm or refute the possibility that treatment in type I patients might have increased rather than decreased fracture incidence. While this study provided information about the BMD and fracture response of OI adults to bisphosphonate treatment, it did not conclusively answer the question as to whether adult OI patients should be treated with bisphosphonates. Certainly the response in adults differs from that in children, and this should be incorporated in the clinical decision as to whether bisphosphonate treatment is appropriate for an individual patient.43 Bradbury et al. studied 32 adults (mean age 39 years) with OI type I who were treated with oral risedronate, 35 mg weekly, for 24 months; 27 completed the study. Primary outcome measures were BMD changes at lumbar spine (LS) and total hip (TH). Secondary outcome measures were fracture incidence, bone pain and change in bone turnover markers (serum procollagen type I aminopropeptide (P1NP) and bone ALP). All participants had multiple low-trauma fragility fractures at an early age and blue sclerae, and most participants had a family history of OI type I. BMD increased at LS by 3.9% (0.815 vs. 0.846 g/cm2, p = 0.007; mean Z-score, −1.93 vs. −1.58, p = 0.002), with no significant change at TH. P1NP fell by 37% (p = 0.00041), with no significant change in bone ALP (p = 0.15). Bone pain did not change significantly (p = 0.6). Fracture incidence remained high, with 25 clinical fractures and 10 major fractures in 14 participants (0.18 major fractures per person per year), with historical data of 0.12 fractures per person per year. The meta-analysis did not demonstrate a significant difference in fracture incidence in patients with OI treated with oral bisphosphonates. During the 2-year study period, data were available for 27 participants. Twenty-five clinically apparent fractures occurred in 14 participants. Ten major fractures occurred in eight participants. The overall major fracture incidence rate was 0.18 major fractures per person per year. Three of five postmenopausal women participating in this study had a major fracture: two women fractured a femur and one fractured her humerus and a vertebra. Excluding postmenopausal women, seven major fractures occurred in five of the remaining 23 participants, giving an incidence rate of 0.15 major fractures per person per year. Two participants who had not recalled any fractures in the preceding 5 years had a major fracture during follow-up. The

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authors concluded that risedronate in adults with OI type I results in modest but significant increases in BMD at the lumbar spine and decreased bone turnover. However, this did not make a clinically significant difference to fracture incidence.44 In summary, in contrast to postmenopausal osteoporosis, no study to date has demonstrated a significant decrease in fracture rate in adults with OI treated with bisphosphonates either orally or IV.

TERIPARATIDE TREATMENT IN ADULT OI Parathryroid hormone (PTH) increases osteoblast bone formation.45 In addition, PTH inhibits sclerostin expression by bone osteocytes thus stimulating bone formation.46 Teriparatide (rh1-34 parathyroid hormone) is an effective treatment for postmenopausal osteoporosis.47 A randomized, double-blinded, placebo-controlled trial of teriparatide, 20 µg daily, administered SQ daily for 18 months to patients with OI was recently completed by Orwoll et al. (Figure 55.3).48 Teriparatide therapy in adults with OI resulted in: (1) changes in biochemical parameters of bone turnover similar to those observed in similar studies in patients with osteoporosis; (2) increases in areal BMD at the hip and spine; (3) a substantial increase in volumetric spine BMD and calculated finite element analysis of spine strength and a decrease in spine load-tostrength ratio; and (4) although the study was not specifically powered to assess fracture incidence, there was no significant change in the incidence of fracture. Clinical fractures were reported by 14 (36%) in the placebo and 11 (29%) of the teriparatide-treated group (P = 0.63). The teriparatide group had non-significantly lower odds of fracture 0.73 (RR: 0.28–1.90). Larger numbers of study patients are required to confirm these results. The mode of action of teriparatide is to increase osteoblast bone formation. However, because in OI it is the osteoblast, the source of type I collagen synthesis, which is compromised, these results suggest that the lack of a teriparatide effect on fracture rate may reflect a limited response based on the alteration in osteoblast collagen metabolism.

AGENTS UNDER STUDY WITH POTENTIAL APPLICATION TO OI (CIRCA DECEMBER 2012) Anti-Sclerostin Antibodies The Wnt signaling pathway is essential to the regulation of osteoblast function. The SOST gene encodes for sclerostin, a protein expressed by osteocytes that

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55.  Osteogenesis Imperfecta: Maintenance of Adult Bone Health

Spine BMD (g/cm2)

(B) 30

Strength*

Trab*

Phi*

8 6.0

6

20

–

–

4.6

4 2.1

2

1.0

0

0.5

0.0

FE measure (% change)

Mean percent change from baseline, SE

(A)

10

0

–10

–2 0

6

12 18 Time on study (months)

Treatment Placebo *P <0.05 between groups **P <0.001 between groups

–20

Treatment Placebo

Figure: Compare percent change in strength, Trab and Phi 18 months from baseline in subjects with treatment or Placebo. *P <0.05 between groups **P <0.001 between groups

FIGURE 55.3  (A) Response to treatment with teriparatide: BMD values for spine L1–L4, in 77 adults with OI mean age 41 years (18–75

range). OI type I = 51; OI type III = 14; OI type IV = 12. Compared to placebo, teriparatide treatment improved lumbar spine BMD. (B) QCT studies including finite element analysis of bone.48 Teriparatide improved calculated bone strength measurement by finite element analysis, and improved trabecular bone mass by QCT. Treatment decreased the calculated phi measurement which represents a positive effect on bone strength. This figure is reproduced in color in the color plate section. (From Orwoll, E. et al. Teriparatide improves BMD and bone strength in adults with osteogenesis imperfecta: a randomized, blinded, placebo controlled trial. Amer J Bone Mineral Res 2012;27:Suppl 1.)

downregulates osteoblastic bone formation via the Wnt pathway; receptors for the protein sclerostin on the osteoblast exert a negative effect on bone formation.45 This function was revealed by loss-of-function mutations in the SOST gene in Van Buchem disease which is characterized by osteosclerosis, and SOST mutations in otherwise healthy individuals found to have increased bone mass secondary to decreased sclerostin formation.49,50 Clinical trials are in progress testing the effect of anti-sclerostin antibodies (Scl-Ab) as anabolic agents in individuals with osteoporosis. Anti-sclerostin antibodies have been studied in animal models of OI. As reported by Sinder et al., two weeks of Scl-Ab successfully stimulated osteoblast bone formation in Brtl/+ and WT mice, leading to improved bone mass and reduced long-bone fragility. Image-guided nanoindentation revealed no alteration in local tissue mineralization dynamics with Scl-Ab.51 Additional reports of Scl-Ab studies in OI mouse models are published in abstract form (2012 Annual Meeting of the American Society for Bone and Mineral Research, Minneapolis). The therapeutic effect of anti-sclerostin Ab in adults with OI is currently under study (F. Glorieux, personal communication).

References [1] Manolagas SC, Parfitt AM. For whom the bell tolls: distress signals from long-lived osteocytes and the pathogenesis of metabolic bone diseases. Bone 2013;54(2):272–8.

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